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...ceptor density at the cell surface resulting in signalsattenuation. Proteins could be endocytosed by utilizingsclathrin-mediated pathway, caveolae-mediated pathway,smacropinocytosis, and phagocytosis =-=[19]-=-. The MUC1sutilizes these pathways for endocytosis and cell surfaceslocalization [20-22] (Fig. 1). Like other glycoproteins,sMUC are also sorted after their internalization in thesearly or sorting end...

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...ce in breast cancer [99, 100]. One of thesmechanism by which Herceptin functions is by bindingsto the extracellular domain of HER2, and inducing itssinternalization for lysosomal mediated degradation =-=[101]-=-.sTherefore, by inhibiting MUC and HER2 interaction bysdesigning peptides against their interacting motifs couldsincrease the efficacy of Herceptin therapy. Recent studyshas shown that administration ...

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...-3 overexpression (Fig. 1) [73]. Galectin-3sis predominantly expressed as a cytosolic protein insepithelial tissues, though it can also localize to thesnucleus, mitochondria and extracellular regions =-=[74]-=-. Inspancreatic cancer, silencing of galectin-3 has shown tosenhance the cell surface interaction between MUC1 andsEGFR in the absence of EGF stimulation and reducedsthe rate of endocytosis of MUC1-EG...

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...f and has been implicated in γ-catenin nuclearslocalization [43]. A similar potential NLS is also presentsin MUC16-CT, but it is yet to be investigated for itssrole in MUC 16-CT nuclear translocation =-=[44]-=-. In breastscancer cell lines, FGF1 has been found to facilitate thestargeting of MUC1-C to the nucleus [45]. FGF1 inducedsthe phosphorylation of MUC1 on Tyr46 residue, whichsFigure 2: Mechanisms of i...

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...he β-cateninsbinding motif inhibits the interaction between MUC1 andsβ-catenin [85]; whereas c-Src mediated phosphorylation ofsthe tyrosine residue in that same SPYEKV site enhancesstheir interaction =-=[86]-=-. MUC1 shows binding affinity to thesArmadillo repeats and the non-repetitive COOH-terminalsregion of β-catenin [87]. MUC1 and β-catenin, once inscomplex, mitigates GSK-3β phosphorylation of β-catenin...

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...MUC, including MUC1, MUC3, MUC16, and MUC17sare cleaved at their evolutionary conserved SEA domainsby an unidentified intracellular protease, changes in pH,sionic concentrations and mechanical stress =-=[4,23,24]-=-.sThe cleaved extracellular domains (ECD) are sheddedsto rapidly clear cell surface associated materials orscolonized/associated pathogens [25,26]. MUC that do notshave the SEA domain e.g., MUC2, MUC4...

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...increased cell surface MUC1 expressionsin lower grade and estrogen receptor (ER)-positive tumorsshave better prognosis, whereas MUC1 cytoplasmicslocalization in tumors correlated with worse prognosis =-=[37]-=-.sAberrant cytoplasmic MUC1 localization has also beenscorrelated with high-risk papillary thyroid carcinoma [38].sIn breast ductal adenocarcinomas, MUC2 and MUC5ACsare localized in cytoplasm with gra...

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...epsin D andscathepsin L. These cathepsins can functions even atsa neutral cytosolic pH and have the ability to activatesapoptotic effectors such as calpains and caspases toselicit apoptotic processes =-=[55]-=-. However, MUC1soverexpression followed by its cleavage to generate MUC1-Csis very well utilized by cancer cells to protect them fromsharsh apoptotic programs. Hence, altered localization of MUC1-C to...

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...lating membrane trafficking is not assclear. The palmitoylation and depalmitoylation status permitsH-Ras and G protein subunits to transduce signals fromsintracellular compartments like Golgi complex =-=[72]-=-. From asclinical perspective, it may be worthwhile to design targetedstherapies against palmitoylation regulating enzymes. DIFFERENTIAL INTERACTION OFsMUCINS WITH PROTEINS UNDERsPATHOLOGICAL CONDITIO...

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...ylation ofsthe tyrosine residue in that same SPYEKV site enhancesstheir interaction [86]. MUC1 shows binding affinity to thesArmadillo repeats and the non-repetitive COOH-terminalsregion of β-catenin =-=[87]-=-. MUC1 and β-catenin, once inscomplex, mitigates GSK-3β phosphorylation of β-cateninsand translocate to the nucleus to transcriptionally activatesvarious genes implicated in increased carcinogenicspot...

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... have been correlated with increasedsmetastatic potential of cancer cell [64–67]. Similarly,selevated sialyl-Lewisx (SLex) epitope has been associatedswith the poor prognosis of colon cancer patients =-=[68]-=-. Insaddition, due to the presence of SLex epitopes on selectinsligands, the unusual higher levels of sialylation of MUCscould play a critical role in the invasion and metastasissof cancer cells [69] ...

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... the absence of a classical mitochondrialslocalization signal, MUC1-C gets localized to the outersmembrane of mitochondria by its interaction with cytosolicschaperones such as the HSP70 and the HSP90 =-=[51]-=- (Fig.s2B). MUC1-C mitochondrial localization has beenscorrelated with the diminished cell death response tosthe DNA damage and other cellular stress by inhibitingsthe release of cell-death causing fa...

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...ria. Interestingly, Heregulins(HRG), a ligand of EGFR family receptor family,senhances the association between MUC1-C and HSP90sdue to autophosphorylation and activation of c-Src insHCT116/MUC1 cells =-=[52]-=- and facilitates the translocationsof MUC1-C to the mitochondria. In breast cancer cells,sFGF1 plays similar role in the mitochondrial localizationsof MUC1 using similar molecular mechanism [45]. Take...

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...6]. In addition, MUC4 is also overexpressed insbreast, gastric and ovarian cancer [7-9], and its overexpressionshas been associated with the poor prognosis of pancreaticscancer and cholangiocarcinoma =-=[10, 11]-=-. However, MUC4sexpression is down-regulated during prostate carcinomass[12] and urothelial cancer [13], suggesting the complicatedscontext-dependent role of mucins. Another example, MUC1sis overexpre...

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...ors [94]. A recent report indicated that ascovalent linkage between a glycosylated MUC1-derivedsglycopeptide and a Toll-like receptor agonist couldselicit strong humoral and cellular immune responsess=-=[103]-=-. Technological advancements, particularly in masssspectrometry, have enabled the characterization of thesentire structure of O-glycans. It would be interesting tosdetermine the structural differences...

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...6]. In addition, MUC4 is also overexpressed insbreast, gastric and ovarian cancer [7-9], and its overexpressionshas been associated with the poor prognosis of pancreaticscancer and cholangiocarcinoma =-=[10, 11]-=-. However, MUC4sexpression is down-regulated during prostate carcinomass[12] and urothelial cancer [13], suggesting the complicatedscontext-dependent role of mucins. Another example, MUC1sis overexpre...

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...MUC1 localization has also beenscorrelated with high-risk papillary thyroid carcinoma [38].sIn breast ductal adenocarcinomas, MUC2 and MUC5ACsare localized in cytoplasm with granular staining patterns=-=[14, 39, 40]-=-, whereas distribution of MUC5B expressionschanges from apical localization in non-malignant breastscells to cytoplasmic and non-apical localization in malignantsductal breast carcinoma [41]. Similarl...

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...r speckles,sarea which is primarily associated with the complex andscrucial process of splicing [48]. Intriguingly, MUC1spost-transcriptionally stabilizes galectin-3 expression insbreast cancer cells =-=[49]-=-, which was attributed to MUC1smediated suppression of microRNA-322 expression.sNevertheless, miRNA independent mechanisms couldsalso be involved, as suggested by the presence ofsMUC1-N in the nuclear...

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...urface under cancerous conditions. The immaturesepisialin is convertible to mature form by addition of sialicsresidues through consecutive internalization and routingsof the MUC1 to the TGN (Fig. 2D) =-=[62]-=-. The half-lifesof MUC1 at the plasma membrane has been calculatedsto be 16–24 h [63], and each round of sialylation takessaround 2.5 hours [62], which suggests that MUC1spossibly undergo recycling ab...

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...ly, phosphorylationsof the serine residue in SPYEKV sequence by glycogenssynthase kinase 3β (GSK3β), a site adjacent to the β-cateninsbinding motif inhibits the interaction between MUC1 andsβ-catenin =-=[85]-=-; whereas c-Src mediated phosphorylation ofsthe tyrosine residue in that same SPYEKV site enhancesstheir interaction [86]. MUC1 shows binding affinity to thesArmadillo repeats and the non-repetitive C...

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... Rab31 overexpression inducessMUC1-C expression [92]. Rab expression profiles aresmodulated under different disease conditions, such assRab25 expression is altered in breast and colorectalscarcinomas =-=[95, 96]-=-, and induce the invasive ability ofscancer cells by interfering with the endosomal traffickingsof cell adhesion proteins such as β-intergrins [97, 98].sSmall molecular inhibitors that target promoter...

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...restricted confinement at the apical surface. Thissallows them to interact with cell surface proteins suchsas the EGFR family members, which normally exist atsthe basolateral sides of polarized cells =-=[76, 77]-=-. MUC4shas shown to interact with HER2/ErbB2 in ovarian andspancreatic cancers [76, 78]. MUC4-ErbB2 complex leadsto the activation of various signaling pathways leadingsto cell proliferation and survi...

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...y of cancer cells. GO-201 and GO-202 are two small peptidessthat recognize the CQC motif in the amino terminal ofsMUC1-C responsible for the translocation of MUC1-Csto various sub-cellular organelles =-=[94]-=-. Both GO-201sand GO-202 showed anti-tumorigenic functions in vitrosand in xenograft models [94]. Targeting the endocyticsvesicles to compartment specific localizations can alsosbe accomplished by mod...

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...lization ofsEGFR and directs it to the nucleus for transcriptionalsupregulation of oncogenic factors [47]. Presencesof MUC4 and MUC1-C has also been related withsHerceptin resistance in breast cancer =-=[99, 100]-=-. One of thesmechanism by which Herceptin functions is by bindingsto the extracellular domain of HER2, and inducing itssinternalization for lysosomal mediated degradation [101].sTherefore, by inhibiti...

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...ase the efficacy of Herceptin therapy. Recent studyshas shown that administration of GO-203 downregulatessthe levels of phospho-p27 and cyclin-E, which abrogatessHerceptin resistance in breast cancer =-=[102]-=-. As MUC4sis one of the most differentially expressed proteins inspancreatic cancer and has been associated with thesHerceptin resistance in breast cancer; the failure of HER2strial in pancreatic canc...

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...s in pH,sionic concentrations and mechanical stress [4,23,24].sThe cleaved extracellular domains (ECD) are sheddedsto rapidly clear cell surface associated materials orscolonized/associated pathogens =-=[25,26]-=-. MUC that do notshave the SEA domain e.g., MUC2, MUC4, MUC5AC arespostulated to get cleaved at their GDPH (Gly-Asp-Pro-His)ssequence [27-29]. The substitution of the aspartic residueswith glutamic re...

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...s in pH,sionic concentrations and mechanical stress [4,23,24].sThe cleaved extracellular domains (ECD) are sheddedsto rapidly clear cell surface associated materials orscolonized/associated pathogens =-=[25,26]-=-. MUC that do notshave the SEA domain e.g., MUC2, MUC4, MUC5AC arespostulated to get cleaved at their GDPH (Gly-Asp-Pro-His)ssequence [27-29]. The substitution of the aspartic residueswith glutamic re...

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...equence [27-29]. The substitution of the aspartic residueswith glutamic residue in the GDPH sequence, which leadssto the lengthening of the side chain by one carbon, hassshown to abolish the cleavage =-=[29]-=-. Acidic environmentsof endoplasmic reticulum plays an important role insGDPH cleavage, though different MUC require differentspH for the cleavage. For example, MUC2 cleavage issstimulated at pH less ...

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...once inscomplex, mitigates GSK-3β phosphorylation of β-cateninsand translocate to the nucleus to transcriptionally activatesvarious genes implicated in increased carcinogenicspotential and metastasis =-=[88]-=-. In breast and colon cancers,sHRG stimulation facilitates the binding between MUC1CT and γ-catenin, allowing MUC1 to function as a vehiclesfor γ-catenin nuclear translocation [43]. These findingssind...

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...MUC1 localization has also beenscorrelated with high-risk papillary thyroid carcinoma [38].sIn breast ductal adenocarcinomas, MUC2 and MUC5ACsare localized in cytoplasm with granular staining patterns=-=[14, 39, 40]-=-, whereas distribution of MUC5B expressionschanges from apical localization in non-malignant breastscells to cytoplasmic and non-apical localization in malignantsductal breast carcinoma [41]. Similarl...

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... survival and proliferative advantages to thescancer cells by inducing the transcription of other proteinsssuch as cyclinD1 and c-myc in a TCF/LEF familysmember-dependent transcriptional upregulation =-=[50]-=-. Mitochondrial translocation of MUC1 Despite the absence of a classical mitochondrialslocalization signal, MUC1-C gets localized to the outersmembrane of mitochondria by its interaction with cytosoli...

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...hanismsas used for mitochondrial localization (Fig. 2C) [53].sLoss of HSP70 is associated with increased intracellularsCa2+ levels and lysosomal permeability, causing deathsof pancreatic cancer cells =-=[54]-=-. However, the exactsmechanism of such HSP70 mediated protection was notsknown. In a recent study, Banerjee et al. have shownsthat HSP70 prevents lysosomal permeabilization by itssphysically interacti...

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...ed of proline,styrosine and serine residues and serve as sites for extensivesO-linked glycosylation, which contributes up to 80%sof their molecular weight and imparts most of their antigenicsepitopes =-=[56]-=-. Inhibition of O-glycosylation by 1-benzyl-2acetamido-2-deoxy-α-d-galactopyranoside (GalNAcα-O-bn)simpedes the apical targeting of glycoproteins by inhibitingsthe docking/fusion of protein carrying v...

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...rface proteins suchsas the EGFR family members, which normally exist atsthe basolateral sides of polarized cells [76, 77]. MUC4shas shown to interact with HER2/ErbB2 in ovarian andspancreatic cancers =-=[76, 78]-=-. MUC4-ErbB2 complex leadsto the activation of various signaling pathways leadingsto cell proliferation and survival through stimulationsof p38 MAPK phosphorylation [79]. In the absence ofsthe soluble...

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...ures have shown twofold higher rate of endocytosis via the hypertonic-mediassensitive clathrin-mediated pathway, along with increasedsintracellular sequestration, as compared to the mature [35S]sMUC1 =-=[20, 21]-=-. Interestingly, this increased internalizationsof truncated MUC1 was not followed by its degradation.sApart from clathrin-mediated endocytosis, a separatesstudy has shown that MUC1 can also be endocy...

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...MUC, including MUC1, MUC3, MUC16, and MUC17sare cleaved at their evolutionary conserved SEA domainsby an unidentified intracellular protease, changes in pH,sionic concentrations and mechanical stress =-=[4,23,24]-=-.sThe cleaved extracellular domains (ECD) are sheddedsto rapidly clear cell surface associated materials orscolonized/associated pathogens [25,26]. MUC that do notshave the SEA domain e.g., MUC2, MUC4...

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...c environmentsof endoplasmic reticulum plays an important role insGDPH cleavage, though different MUC require differentspH for the cleavage. For example, MUC2 cleavage issstimulated at pH less than 6 =-=[27]-=-, whereas MUC5ACscleavage has been demonstrated to occur at neutral pH ofsendoplasmic reticulum [29]. Nevertheless, the cleavage ofsthe MUC5AC mucin is augmented at lower pH. The pathways of MUC traff...

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... their inhibitionsattenuates secretion of MUC [34]. Synaptotagmins,sa family of low affinity Ca2+ sensor proteins, are alsosinvolved in more than 90% of acute MUC secretion uponsextracellular signals =-=[35]-=-. Oncotarget7274www.impactjournals.com/oncotarget ALTERED LOCALIZATION OF MUC Cytoplasmic localization and its associationswith disease In 1992, Ceriani and colleagues conducted immunohistochemistry (...

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...ocalization on 227 breast cancerspatients. They found that low cytoplasmic intensity andshigh cell surface localization of MUC1 correlated withsbetter prognosis of breast cancer patients and survivals=-=[36]-=-. This observation was further validated by Rahn et al.,swho found that increased cell surface MUC1 expressionsin lower grade and estrogen receptor (ER)-positive tumorsshave better prognosis, whereas ...

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...nosis, whereas MUC1 cytoplasmicslocalization in tumors correlated with worse prognosis [37].sAberrant cytoplasmic MUC1 localization has also beenscorrelated with high-risk papillary thyroid carcinoma =-=[38]-=-.sIn breast ductal adenocarcinomas, MUC2 and MUC5ACsare localized in cytoplasm with granular staining patterns[14, 39, 40], whereas distribution of MUC5B expressionschanges from apical localization in...

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...al localization in malignantsductal breast carcinoma [41]. Similarly, MUC3 cell surfacesexpression has been correlated with poor prognosis, highersgrade and negative ER expression in breast carcinoma =-=[42]-=-.sThese studies clearly demonstrate that, aberrant localizationsof MUC is associated with cancer pathology [14, 36, 38, 39],sFigure 1: Diagrammatical representation of the intracellular transport of g...

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... MUC16-CT, but it is yet to be investigated for itssrole in MUC 16-CT nuclear translocation [44]. In breastscancer cell lines, FGF1 has been found to facilitate thestargeting of MUC1-C to the nucleus =-=[45]-=-. FGF1 inducedsthe phosphorylation of MUC1 on Tyr46 residue, whichsFigure 2: Mechanisms of intracellular transport and sorting of MUC1. MUC1 has demonstrated to be internalization by usingsclathrin an...

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...he plasmasmembrane, as this inhibitor interferes with the localizationsof proteins involved in apical trafficking such as, the apicalst-SNARE, syntaxin-3 and the raft-associated protein annexinsXIIIb =-=[57]-=-. Besides O-glycosylation, MUC also containspotential N-glycosylation sites. For example; MUC13shave seven N-glycosylation sites [58]. N-glycosylation ofsMUC plays important roles in their folding, so...

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...st-SNARE, syntaxin-3 and the raft-associated protein annexinsXIIIb [57]. Besides O-glycosylation, MUC also containspotential N-glycosylation sites. For example; MUC13shave seven N-glycosylation sites =-=[58]-=-. N-glycosylation ofsMUC plays important roles in their folding, sorting, andssecretion [59]. Studies have demonstrated that absence ofsN-glycosylation blocks the apical targeting of glycoproteins,swh...

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...outsinterfering or altering the rate of its endocytosis [17].sStudies have also revealed the importance of tyrosinesresidues at position 20 and 60 in the MUC1-CT domain,sin the process of endocytosis =-=[70]-=-. The Y20N mutation insassociation with the CQCRRK motif inhibit the interactionsof MUC1 with the adaptor proteins AP-1 and AP-2,swhereas the Y60N mutation inhibits MUC1 associationswith another adapt...

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...HOLOGICAL CONDITION Additional factors may also modulate theslocalization of MUC under cancerous conditions. Onesexample is the differential MUC interactions due tosgalectin-3 overexpression (Fig. 1) =-=[73]-=-. Galectin-3sis predominantly expressed as a cytosolic protein insepithelial tissues, though it can also localize to thesnucleus, mitochondria and extracellular regions [74]. Inspancreatic cancer, sil...

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...restricted confinement at the apical surface. Thissallows them to interact with cell surface proteins suchsas the EGFR family members, which normally exist atsthe basolateral sides of polarized cells =-=[76, 77]-=-. MUC4shas shown to interact with HER2/ErbB2 in ovarian andspancreatic cancers [76, 78]. MUC4-ErbB2 complex leadsto the activation of various signaling pathways leadingsto cell proliferation and survi...

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...ian andspancreatic cancers [76, 78]. MUC4-ErbB2 complex leadsto the activation of various signaling pathways leadingsto cell proliferation and survival through stimulationsof p38 MAPK phosphorylation =-=[79]-=-. In the absence ofsthe soluble ligand, the MUC4-ErbB2 complex leadssto ErbB2 phosphorylation, which in turn, leads to thesphosphorylation of the ErbB2-ErbB3 heterodimer in thespresence of neuregulin ...

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.... In the absence ofsthe soluble ligand, the MUC4-ErbB2 complex leadssto ErbB2 phosphorylation, which in turn, leads to thesphosphorylation of the ErbB2-ErbB3 heterodimer in thespresence of neuregulin =-=[80]-=-. MUC4 did not demonstratesinteraction with ErbB3 in polarized cells, but loss ofspolarity facilitates MUC4-ErbB3 interaction. The tradeoff between phosphorylation andsglycosylation (O-GlcNAc) is know...

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...reased EGFR recycling back to the plasma membranes[77]. Likewise, MUC4 has also shown to interact withsthe other EGFR family member, HER2, via its EGF-likesmotifs located at the juxtamembrane domains =-=[82]-=-. ThesEGF-like motif is also present in other MUC like MUC17swhich has been implicated in the pathogenesis of colonicsinflammation and cancer, and can presumably initiatessEGFR mediated oncogenic sign...

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.../oncotarget of β-catenin and E-cadherin, and was linked with greaterscellular motility and invasiveness [89]. In agreement,sreduction of MUC16 expression has been related withsadvanced ovarian cancer =-=[91]-=-. Taken together, thesesstudies pointed towards the possibility that the interactionssbetween MUC16, E-cadherin and/or β-catenin permitsMUC16 to modulate various signaling pathways. Bitler et al. foun...

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...the presencesof transmembrane domain, whereas secretory mucinss(such as MUC2, MUC5AC, MUC5B) get packagedsinto secretory vesicles and released upon receivingsappropriate extracellular signal (Fig. 1) =-=[4]-=-. MUC havesdifferent physicochemical properties due to the presencesof different domains like nidogen-like domain (NIDO),ssea urchin sperm protein–enterokinase–agrin (SEA), vonsWillebrand factor D dom...

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...r [7-9], and its overexpressionshas been associated with the poor prognosis of pancreaticscancer and cholangiocarcinoma [10, 11]. However, MUC4sexpression is down-regulated during prostate carcinomass=-=[12]-=- and urothelial cancer [13], suggesting the complicatedscontext-dependent role of mucins. Another example, MUC1sis overexpressed in various malignancies and inflammatorysconditions [1, 14-16]. Besides...

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...erexpressionsof MUC, emerging evidence suggests that anomalies instheir subcellular localization and resultant changes in theirsendocytic trafficking play critical roles under pathologicalsconditions =-=[17]-=-. In a cell, majority of proteins are not pre-set to anyssingle location and are in a steady-state distribution due tosopposing egress (exocytosis) and entrance (endocytosis)sOncotarget7273www.impactj...

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...volved in this apicalstargeting. It has been observed that epithelial cancers expressessMUC1 with truncated or under-glycosylated glycans,ssuch as the Tn (GalNAcα-) and TF (Galβ1, 3GalNAcα-)santigens =-=[21]-=-. Comparison of the stability of thesdifferentially glycosylated forms of MUC1, derived fromsnormal CHO cells and UDP-glucose-4-epimerase deficients(glycosylation-defective) ldlD cells, revealed that ...

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...rnalizationsof truncated MUC1 was not followed by its degradation.sApart from clathrin-mediated endocytosis, a separatesstudy has shown that MUC1 can also be endocytosedsvia macropinocytosis (Fig. 1) =-=[22]-=-, which suggests thesinvolvement of multiple endocytic pathways in MUC1sinternalization. These observations raise questions, suchsas: whether the alternative pathway of internalization issresponsible ...

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...C2 occurs in the endoplasmic reticulum duesto formation of disulfide bonds in the cysteine knotsdomain [30] and the subsequent trimerization occur bysforming disulfide bonds in the vWD3 domain in TGNs=-=[31]-=-. MUC2 and possibly other gel forming secretorysMUC form large net-like structures, required to protectsepithelia from various harsh conditions. The densespacking of MUC2 in secretory granules occurs ...

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...ired to protectsepithelia from various harsh conditions. The densespacking of MUC2 in secretory granules occurs due to thesformation of large aggregates under high Ca2+ and low pHsconditions (Fig. 1) =-=[32]-=-. Calcium depletion and HCO3-smediated pH neutralization can unfold these aggregatessand tightly clumped MUC. The HCO3- ion transportationsacross the plasma membrane occurred by cysticsfibrosis transm...

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...e,scalcium-activated chloride channel 3, and cysteine stringsprotein and heat shock protein (HSP) 70. These proteinsare considered to be highly crucial as their inhibitionsattenuates secretion of MUC =-=[34]-=-. Synaptotagmins,sa family of low affinity Ca2+ sensor proteins, are alsosinvolved in more than 90% of acute MUC secretion uponsextracellular signals [35]. Oncotarget7274www.impactjournals.com/oncotar...

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...in a prototypical monopartitesnuclear localization signal (NLS); though it has aspositively charged amino acid stretch known as thesRRK motif and has been implicated in γ-catenin nuclearslocalization =-=[43]-=-. A similar potential NLS is also presentsin MUC16-CT, but it is yet to be investigated for itssrole in MUC 16-CT nuclear translocation [44]. In breastscancer cell lines, FGF1 has been found to facili...

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...has indicatedsthat the ectodomain of MUC1 can also translocate tosthe nucleus, although to different area of the nucleus.sMUC1-C localization to the nuclear periphery, nucleolarsand in nuclear matrix =-=[47]-=-, whereas, the ectodomain ofsMUC1 or MUC1-N localizes to the nuclear speckles,sarea which is primarily associated with the complex andscrucial process of splicing [48]. Intriguingly, MUC1spost-transcr...

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... nucleolarsand in nuclear matrix [47], whereas, the ectodomain ofsMUC1 or MUC1-N localizes to the nuclear speckles,sarea which is primarily associated with the complex andscrucial process of splicing =-=[48]-=-. Intriguingly, MUC1spost-transcriptionally stabilizes galectin-3 expression insbreast cancer cells [49], which was attributed to MUC1smediated suppression of microRNA-322 expression.sNevertheless, mi...

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...polarized Madin-Darby canine kidneysepithelial cells (MDCK) and non-polarized Chinese hamstersOncotarget7277www.impactjournals.com/oncotarget ovary (CHO) cells and make them proteolytically sensitives=-=[60]-=-. However, due to unresolved issues including that ofscell specificity have so far precluded the identificationsof specific glycan determinants involved in this apicalstargeting. It has been observed ...

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...UC1 targetedsantigens. Further, Razawi et al have suggested that membranelocalized and secretory MUC1, both have altered O-glycanscore structures, due to the differential pathway of theirstrafficking =-=[61]-=-. Authors utilized recombinant epitopetagged MUC1 (MUC1-M), mutants with defectivesclathrin-mediated endocytosis (MUC1-M-Y20,60N) andsmutants with recycling defects (palmitoylation-defectivesMUC1-M-CQ...

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...rm by addition of sialicsresidues through consecutive internalization and routingsof the MUC1 to the TGN (Fig. 2D) [62]. The half-lifesof MUC1 at the plasma membrane has been calculatedsto be 16–24 h =-=[63]-=-, and each round of sialylation takessaround 2.5 hours [62], which suggests that MUC1spossibly undergo recycling about 9–10 times. The multiplesrounds through TGN generate abnormally high levels ofssi...

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... the noticeable cell surface localization of MUC1.sHowever, presence of EGF stimulation leads to the nuclearstranslocation of EGFR without affecting MUC1 cellssurface and MUC1-CT nuclear localization =-=[75]-=-. Uponsrescuing this knockdown effect by recombinant galectin-3,sdiscernible redistribution of MUC1 from the cell surfacesto the cytoplasm was observed [75]. Therefore, galectin-3soverexpression in ca...

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...sults in the release ofsintracellular MUC1-CT to regulate MUC1 mediatedscellular proliferation [83]. The MUC1-CT and E-cadherinsboth compete for β-catenin binding due to the loss ofscellular polarity =-=[45, 84]-=-. Like EGFR family members, β-catenin also residessat the lateral side of the cell. The loss of polarity allowssβ-catenin to interact with the SAGNGGSSL motifspresent in MUC1-C and the loss of E-cadhe...

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.... These findingssindicate that MUC1-CD has crucial functions in integratingssignals from the EGFR and Wnt signaling pathways.sUnlike in MUC1 and MUC4, the RTK binding motif is notspresent in MUC16-CT =-=[89]-=-. However, MUC16 secretionsis influenced by EGF stimulation through phosphorylationsof MUC16-CT [90]. MUC16 knockdown in ovarianscancer cell lines caused increased cytoplasmic localizationsOncotarget7...

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... Rab31 overexpression inducessMUC1-C expression [92]. Rab expression profiles aresmodulated under different disease conditions, such assRab25 expression is altered in breast and colorectalscarcinomas =-=[95, 96]-=-, and induce the invasive ability ofscancer cells by interfering with the endosomal traffickingsof cell adhesion proteins such as β-intergrins [97, 98].sSmall molecular inhibitors that target promoter...

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...n is altered in breast and colorectalscarcinomas [95, 96], and induce the invasive ability ofscancer cells by interfering with the endosomal traffickingsof cell adhesion proteins such as β-intergrins =-=[97, 98]-=-.sSmall molecular inhibitors that target promoters of thesesRab and other trafficking proteins could be designedsto reroute MUC to the degradation pathways. Otherssmall molecular inhibitors like gelda...

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...lization ofsEGFR and directs it to the nucleus for transcriptionalsupregulation of oncogenic factors [47]. Presencesof MUC4 and MUC1-C has also been related withsHerceptin resistance in breast cancer =-=[99, 100]-=-. One of thesmechanism by which Herceptin functions is by bindingsto the extracellular domain of HER2, and inducing itssinternalization for lysosomal mediated degradation [101].sTherefore, by inhibiti...

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...sionshas been associated with the poor prognosis of pancreaticscancer and cholangiocarcinoma [10, 11]. However, MUC4sexpression is down-regulated during prostate carcinomass[12] and urothelial cancer =-=[13]-=-, suggesting the complicatedscontext-dependent role of mucins. Another example, MUC1sis overexpressed in various malignancies and inflammatorysconditions [1, 14-16]. Besides the aberrant overexpressio...

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...s are not pre-set to anyssingle location and are in a steady-state distribution due tosopposing egress (exocytosis) and entrance (endocytosis)sOncotarget7273www.impactjournals.com/oncotarget pathways =-=[18]-=-. These two pathways are extremely dynamicsand are regulated by highly sensitive cross talks betweensdifferent subcellular compartments. Endocytic pathwaysshave always been considered as enduring mech...

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... in their trafficking occur duesto variability in their domains. For instance, dimerizationsof MUC2 occurs in the endoplasmic reticulum duesto formation of disulfide bonds in the cysteine knotsdomain =-=[30]-=- and the subsequent trimerization occur bysforming disulfide bonds in the vWD3 domain in TGNs[31]. MUC2 and possibly other gel forming secretorysMUC form large net-like structures, required to protect...

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...MUC1 localization has also beenscorrelated with high-risk papillary thyroid carcinoma [38].sIn breast ductal adenocarcinomas, MUC2 and MUC5ACsare localized in cytoplasm with granular staining patterns=-=[14, 39, 40]-=-, whereas distribution of MUC5B expressionschanges from apical localization in non-malignant breastscells to cytoplasmic and non-apical localization in malignantsductal breast carcinoma [41]. Similarl...

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...ns[14, 39, 40], whereas distribution of MUC5B expressionschanges from apical localization in non-malignant breastscells to cytoplasmic and non-apical localization in malignantsductal breast carcinoma =-=[41]-=-. Similarly, MUC3 cell surfacesexpression has been correlated with poor prognosis, highersgrade and negative ER expression in breast carcinoma [42].sThese studies clearly demonstrate that, aberrant lo...

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...C1 Recent report has also demonstrated lysosome assanother subcellular compartment where MUC1-C canslocalize utilizing similar HSP dependent mechanismsas used for mitochondrial localization (Fig. 2C) =-=[53]-=-.sLoss of HSP70 is associated with increased intracellularsCa2+ levels and lysosomal permeability, causing deathsof pancreatic cancer cells [54]. However, the exactsmechanism of such HSP70 mediated pr...

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...tion, MUC also containspotential N-glycosylation sites. For example; MUC13shave seven N-glycosylation sites [58]. N-glycosylation ofsMUC plays important roles in their folding, sorting, andssecretion =-=[59]-=-. Studies have demonstrated that absence ofsN-glycosylation blocks the apical targeting of glycoproteins,swhich results in the accumulation of glycoproteins in thesGolgi complex of polarized Madin-Dar...

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...ns. It is noteworthysthat palmitoylation is an important modification for thesOncotarget7278www.impactjournals.com/oncotarget trafficking of a number of receptors, ion channels andssignaling proteins =-=[71]-=-. The precise mechanism by whichspalmitoylation is regulating membrane trafficking is not assclear. The palmitoylation and depalmitoylation status permitsH-Ras and G protein subunits to transduce sign...

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...3 in polarized cells, but loss ofspolarity facilitates MUC4-ErbB3 interaction. The tradeoff between phosphorylation andsglycosylation (O-GlcNAc) is known to regulatesintracellular trafficking of EGFR =-=[81]-=-. MUC1 is knownsto interact with EGFR at plasma membrane of nonpolarized breast epithelia which resulted in increasedsEGFR internalization, reduced lysosomal degradation andsincreased EGFR recycling b...

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...ith c-Src and β-catenin.sMUC1-CT also has a γ-secretase cleavage motif andsthe cleavage by γ-secretase results in the release ofsintracellular MUC1-CT to regulate MUC1 mediatedscellular proliferation =-=[83]-=-. The MUC1-CT and E-cadherinsboth compete for β-catenin binding due to the loss ofscellular polarity [45, 84]. Like EGFR family members, β-catenin also residessat the lateral side of the cell. The los...

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...d Wnt signaling pathways.sUnlike in MUC1 and MUC4, the RTK binding motif is notspresent in MUC16-CT [89]. However, MUC16 secretionsis influenced by EGF stimulation through phosphorylationsof MUC16-CT =-=[90]-=-. MUC16 knockdown in ovarianscancer cell lines caused increased cytoplasmic localizationsOncotarget7279www.impactjournals.com/oncotarget of β-catenin and E-cadherin, and was linked with greaterscellul...

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...promotersregion [47]. Besides controlling such inter-molecularsinteractions, MUC1-C also regulates Rab31 expression,swhich is an early endosome protein belonging to thessubfamily of small GTPase Rab5 =-=[92]-=-. MUC1-C andsestrogen receptor form a complex at the Rab31 promotersand are responsible for the transcriptional activationsof Rab31. According to this study, patients whosexpress MUC1-C and Rab31 are ...

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... increasesin the sensitivity to cis-diaminedichloroplatinum II (cDDP,scis-platin), carboplatin and other anti-cancer drugs uponsdepletion of the vacuolar protein sorting 33A or thescappuccino protein =-=[93]-=-, which strongly signpost the ideasthat therapeutic targeting of protein trafficking moleculesscan increase the drug sensitivity of cancer cells. GO-201 and GO-202 are two small peptidessthat recogniz...

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...n is altered in breast and colorectalscarcinomas [95, 96], and induce the invasive ability ofscancer cells by interfering with the endosomal traffickingsof cell adhesion proteins such as β-intergrins =-=[97, 98]-=-.sSmall molecular inhibitors that target promoters of thesesRab and other trafficking proteins could be designedsto reroute MUC to the degradation pathways. Otherssmall molecular inhibitors like gelda...