Cell surface-associated mucins in signal transduction

doi:10.1016/j.tcb.2006.07.006

Trends in Cell Biology

Volume 16, Issue 9, September 2006, Pages 467-476

https://doi.org/10.1016/j.tcb.2006.07.006 Get rights and content

Mucins are heavily glycosylated high molecular weight glycoproteins, which are involved in the protection and lubrication of luminal epithelial surfaces. Transmembrane mucins also engage in signal transduction, through extracellular domain-mediated ligand binding or by interacting with receptors for growth and differentiation factors. The cytoplasmic tail of MUC1 (MUC1CT), the best characterized of the transmembrane mucins, is involved in several signaling pathways, including those involving Ras, β-catenin, p120 catenin, p53 and estrogen receptor α. MUC1CT also forms complexes with transcription factors, and then translocates to the nucleus by an unknown mechanism, where it is believed to influence the transcription of their target genes. MUC1CT has also been proposed to localize to mitochondrial membranes under conditions of genotoxic stress, where it attenuates the apoptotic pathway in response and confers resistance to apoptosis-inducing drugs.

Introduction

Mucins are high molecular weight glycoproteins expressed by secretory or polarized epithelia, lining the luminal surfaces of respiratory, gastrointestinal and reproductive tracts [1]. The cellular expression pattern of mucins has led investigators to propose two classifications: membrane-bound mucins and secretory mucins. The secretory mucins, which lack a transmembrane domain and are secreted directly into the extracellular spaces, include MUC2, MUC5AC, MUC5B, MUC6, MUC7, MUC8 and MUC19. The membrane-bound class of mucins are type I membrane proteins with single transmembrane domains and different lengths of cytoplasmic tail at the C-terminus. The membrane-bound class includes MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17 and MUC20. Membrane-bound mucins can be released from cells through proteolytic cleavage, and many are produced in secreted forms that result from alternative mRNA splice forms in which the transmembrane domains are eliminated.

Transmembrane mucins are postulated to serve as sensors of the external environment, through extracellular domain-mediated ligand binding or as a consequence of altered conformations that result from changes in external biochemical conditions (pH, ionic composition, physical interactions). Signals are transmitted to the interior of the cell through post-translational modifications of the cytoplasmic tail that include phosphorylation events, proteolytic events and perhaps other modifications. The cytoplasmic tails of membrane-bound mucins are also hypothesized to be involved in signaling events that contribute to the progression of cancer.

Of the cell-surface mucins, MUC1 is the best characterized with respect to signal transduction, and is the focus here (Box 1). Signals are transmitted to the nucleus by association of the MUC1 cytoplasmic tail (MUC1CT) with agents of signal transduction that include β-catenin, p120 catenin, p53 and estrogen receptor α (ER-α) (Figure 1). Several studies indicate that intercellular adhesion molecule 1 (ICAM-1) might serve as a ligand for MUC1, activating outside-in signaling via the MUC1CT 2, 3, 4. The binding of ICAM-1 to MUC1 can initiate calcium signaling, which is independent of the mitogen-activated protein (MAP) kinase pathway [2]. Another study showed that binding to Pseudomonas aeruginosa or its flagellin protein can serve as an activator of MUC1 signaling by promoting MUC1CT phosphorylation-mediated activation of the MAP kinase pathway [5]. It is likely that there are other unknown ligands for MUC1.

Section snippets

Signaling through MUC1CT

MUC1CT contains 72 residues and harbors several sites that can be phosphorylated; these modulate the binding affinities of different classes of signal transduction elements (Figure 2). Interactions of MUC1 with protein kinases in several different signaling cascades are well characterized and are discussed below.

Nuclear and nucleolar localization of MUC1CT and its interaction with ErbB family members

MUC1CT, as demonstrated by reciprocal coimmunoprecipitations, associates with β-catenin, p120 catenin, p53 and ER-α in the nucleus, where it has been hypothesized to modulate transcriptional events. Chromatin immunoprecipitation (ChIP) assays on MUC1-overexpressing breast cancer cells have shown that the MUC1CT resides on promoter elements of genes regulated by p53. The association of MUC1 with transcriptional regulators at promoters supports the hypothesis that the MUC1CT contributes to

Interaction of the MUC1CT with the Src family of non-RTKs

The Src family includes nine non-RTKs: Src, Yes, Fgr, Yrk, Fyn, Lyn, Hck, Lck and Blk, which share common sequence and structural features. Of the nine family members, c-Src, Lyn and Lck can bind and phosphorylate the MUC1CT of full-length MUC1 at the tyrosine in the YEKV motif 13, 14, 15, 16, 17. The c-Src SH2 domain interacts directly with the YEKV motif and inhibits the binding of glycogen synthase kinase 3β (GSK-3β), which can also phosphorylate the MUC1CT and reduce its interaction with

MUC1 and regulation of the LEF/TCF-dependent Wnt pathway

Wnt signaling regulates the normal developmental program and cell fate along the crypt–villus axis [18]. Wnts, secreted glycoproteins that serve as ligands for the frizzled seven-pass transmembrane receptors, prevent the proteasomal degradation of β-catenin, which interacts with the lymphoid enhancer factor 1 (LEF)/T-cell factor (TCF) family of transcription factors to activate the transcription of Wnt target genes, including cyclin D1 and c-myc. GSK-3β and adenomatous polyposis coli (APC) are

Regulation of the p53 pathway by the MUC1CT

p53 is a major tumor suppressor that helps to regulate antiapoptotic functions, DNA repair and DNA recombination. Most human tumors have either mutations in p53 or defects in the p53 pathway. The MUC1CT (presumably a cleaved form) associates with p53 and contributes to the regulation of DNA damage-induced transcriptional activation of p21, a key player in the promotion of cell-cycle progression and prevention of apoptosis, and to abrogation of the transcription of Bax, which serves proapoptotic

Activation of the MAP kinase pathway by the MUC1CT

The MUC1CT is involved in activation of MAP kinase pathways, through interactions with ErbB receptors, where it potentiates their signaling by enhancing the activation of extracellular-signal-regulated kinases (ERK) 1 and -2 in mouse mammary glands [11]. The MUC1CT of full-length MUC1 also interacts with Grb2–Sos. One hypothesis is that the MUC1CT serves as an adaptor or a scaffold protein that recruits Grb2 to sites in close proximity to ErbB1 in a MUC1CT phosphorylation-dependent manner. The

The MUC1CT causes stabilization of ER-α

ERs, which exist in two main forms (ER-α and ER-β), are ligand-based transcription factors which regulate gene transcription by binding to estrogen response elements (ERE) in DNA [28]. 17β-estradiol (E2) is the most common ER ligand, and exerts its effects on growth, development and homeostasis in different tissues and organs. In breast cancer, MUC1 enhances E2-dependent growth and survival by binding to and stabilizing ER-α, which blocks its proteasomal degradation [29]. The MUC1CT is present

The MUC1CT: at the crossroads between different signaling pathways

The MUC1CT might facilitate unique interactions among different signaling pathways. Although a role for the MUC1CT as a scaffolding protein has not been clearly established, its interaction with components of different signaling pathways raises the possibility that it might serve as a platform for integrating cellular signaling networks. Simultaneous association of the MUC1CT, β-catenin and c-Src has been demonstrated and it is known that c-Src can phosphorylate β-catenin and activate

Regulation of MUC1 endocytosis by the signaling status of the MUC1CT

MUC1 is a heavily glycosylated transmembrane protein, and its membrane trafficking has been shown to be dependent on the glycosylation status of the extracellular subunit 32, 33. However, glycosylation-independent internalization of MUC1 is regulated by signaling motifs in the MUC1CT [34]. The tyrosine in the YHPM motif is crucial for interaction with the clathrin adaptor protein AP-2, whereas tyrosine in the YTNP regulates interaction with the SH2 domain of Grb2-signaling adaptor protein,

The MUC1CT: a regulator of oxidative stress-induced apoptosis

Expression of MUC1 has been shown to modulate apoptosis both in vivo and in vitro 24, 37, 38, 39, 40, 41, 42. Uniparous (having produced a single litter) MMTV–MUC1 transgenic mice show decreased apoptosis postlactation in mammary glands [38]. The MUC1CT activates the PI 3-kinase–Akt pathway and increases the expression of the antiapoptotic protein Bcl-x_L by a PI 3-kinase-independent mechanism in vitro [42]. Overexpression of MUC1 attenuates the apoptotic response to araC and gemcitabine in 3Y1

MUC1CT in triggering immune responses

MUC1 is expressed by some activated T cells, and has been proposed as a downstream effector of T cell receptor ligation and T cell stimulation 43, 44. The MUC1CT of full-length MUC1 is bound and phosphorylated by Lck and ZAP-70 tyrosine kinases, which are activated upon T cell activation 15, 16, 45. Hence, MUC1 can be envisioned to contribute to signaling responses during immune activation. The MUC1CT contains a potential immunoreceptor tyrosine-based activation-like motif (YXXLX₈YXXM), which

Cellular architecture, mucins and signaling

Both MUC1 and MUC4 can interact with tyrosine kinases (Box 3), including the ErbB family of receptors and other RTKs. However, these are expressed at the basolateral surfaces of normal differentiated epithelial cells, which probably precludes physical interactions with MUC1 and MUC4 (expressed at the apical surface of normal epithelial cells) and consequent signaling. A loss of polarity in the epithelial cells, perhaps through a physical or molecular breach in the lateral or basal aspects of

Summary

Mucins are normally distributed on the apical cell surface of epithelia, in contrast to adhesion molecules and growth factor receptors, which are localized on the basal and lateral surfaces of polarized epithelia. Loss of polarized architecture enables association of mucins, RTKs and other signaling molecules, which sends a signal to the nucleus regarding loss of polarity, status of motility and other morphogenetic conditions. These signals are predicted to incite changes in gene transcription

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Trends in Cell Biology

ReviewCell surface-associated mucins in signal transduction

Introduction

Section snippets

Signaling through MUC1CT

Nuclear and nucleolar localization of MUC1CT and its interaction with ErbB family members

Interaction of the MUC1CT with the Src family of non-RTKs

MUC1 and regulation of the LEF/TCF-dependent Wnt pathway

Regulation of the p53 pathway by the MUC1CT

Activation of the MAP kinase pathway by the MUC1CT

The MUC1CT causes stabilization of ER-α

The MUC1CT: at the crossroads between different signaling pathways

Regulation of MUC1 endocytosis by the signaling status of the MUC1CT

The MUC1CT: a regulator of oxidative stress-induced apoptosis

MUC1CT in triggering immune responses

Cellular architecture, mucins and signaling

Summary

J. Biol. Chem.

J. Biol. Chem.

Neuron

Int. J. Radiat. Oncol. Biol. Phys.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Cancer Cell

Biochem. Biophys. Res. Commun.

Mol. Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Cancer Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mucins in cancer: protection and control of the cell surface

Nat. Rev. Cancer

MUC1 synthetic peptide inhibition of intercellular adhesion molecule-1 and MUC1 binding requires six tandem repeats

Cancer Res.

The breast mucin MUCI as a novel adhesion ligand for endothelial intercellular adhesion molecule 1 in breast cancer

Cancer Res.

Pseudomonas aeruginosa stimulates phosphorylation of the airway epithelial membrane glycoprotein Muc1 and activates MAP kinase

Am. J. Physiol. Lung Cell. Mol. Physiol.

Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor

Mol. Cell. Biol.

Review
Cell surface-associated mucins in signal transduction