The c-Src Tyrosine Kinase Regulates Signaling of the Human DF3/MUC1 Carcinoma-associated Antigen with GSK3β and β-Catenin

Li, Yongqing; Kuwahara, Hiroaki; Ren, Junyu; Wen, Gengyun; Küfe, Donald

doi:10.1074/jbc.c000754200

Cited by 214 publications

(222 citation statements)

References 32 publications

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“…There is evidence suggesting that the intracellular targeting of Src is a kinase-independent mechanism that is determined principally by interactions involving the SH3 domain with modulation by the SH2 domain (43). Supporting this, previous studies by Li et al (18) showed that Src interacts with MUC1 via its NH 2 -terminal SH3 domain and is able to phosphorylate the tyrosine residues of MUC1-CD to generate conserved binding sites for SH2-containing proteins. In this report, we found that there was always a minor level of association between Src and MUC1 in both breast cancer cells and MUC1-transfected 293T cells.…”

Section: Discussionsupporting

confidence: 62%

“…The MUC1-CD has seven tyrosine residues, four of which are established phosphorylation sites of protein tyrosine kinases, including Src (12,18,32). Therefore, we postulate that Src kinase activity may be required for recruiting CrkL to the MUC1-CD in the ICAM-1 ligation -induced promigratory signaling.…”

Section: Src Functions Upstream Of Crkl In the Muc1/icam-1 Interactiomentioning

confidence: 97%

“…The 72-amino-acid cytoplasmic domain of MUC1 (MUC1-CD) contains seven highly conserved tyrosine residues, four of which are confirmed phosphorylation sites and construct potential docking motifs for SH2 or SH3 domain -containing proteins, such as Src family kinases and growth factor receptor binding protein 2 (12,13). Thus far, epidermal growth factor receptor (14,15), PKCy (16), and Src (14,17,18) have been found to physically associate with and phosphorylate MUC1-CD. This indicates that MUC1, although without intrinsic kinase activity (19), could function as a scaffold protein in signal transduction.…”

Section: Introductionmentioning

confidence: 99%

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MUC1 Initiates Src-CrkL-Rac1/Cdc42–Mediated Actin Cytoskeletal Protrusive Motility after Ligating Intercellular Adhesion Molecule-1

Shen

Rahn²,

Zhang³

et al. 2008

Molecular Cancer Research

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MUC1, a transmembrane glycoprotein of the mucin family, when aberrantly expressed on breast cancer cells is correlated with increased lymph node metastases. We have previously shown that MUC1 binds intercellular adhesion molecule-1 (ICAM-1) on surrounding accessory cells and facilitates transendothelial migration of MUC1-bearing cells. Nevertheless, the underlying molecular mechanism is still obscure. In the present study, we used a novel assay of actin cytoskeletal reorganization to show that by ligating ICAM-1, MUC1 triggers Rac1-and Cdc42-dependent actin cytoskeletal protrusive activity preferentially at the heterotypic cell-cell contact sites. Further, we show that these MUC1/ICAM-1 interaction -initiated lamellipodial and filopodial protrusions require Src family kinase and CT10 regulator of kinase like (CrkL) accompanied by the rapid formation of a Src-CrkL signaling complex at the MUC1 cytoplasmic domain. Through inhibition of Src kinase activity, we further revealed that Src is required for recruiting CrkL to the MUC1 cytoplasmic domain as well as mediating the observed actin cytoskeleton dynamics. These findings suggest a novel MUC1-Src-CrkL-Rac1/Cdc42 signaling cascade following ICAM-1 ligation, through which MUC1 regulates cytoskeletal reorganization and directed cell motility during cell migration. (Mol Cancer Res 2008;6(4):555 -67)

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Section: Discussionsupporting

confidence: 62%

Section: Src Functions Upstream Of Crkl In the Muc1/icam-1 Interactiomentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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MUC1 Initiates Src-CrkL-Rac1/Cdc42–Mediated Actin Cytoskeletal Protrusive Motility after Ligating Intercellular Adhesion Molecule-1

Shen

Rahn²,

Zhang³

et al. 2008

Molecular Cancer Research

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“…However, a functional role for MUC5B in transformation is not known. Moreover, previous work has shown that MUC1-CD is phosphorylated on Thr-41, Ser-44, Tyr-46 and Tyr-60 by PKCδ, GSK3ß, c-Src and c-Abl, respectively (12,(21)(22)(23). Significantly, none of these phosphorylation sites is present in the MUC5B repeats (Fig.…”

Section: Discussionmentioning

confidence: 85%

“…Overexpression of MUC1-CD is sufficient for the induction of transformation and the interaction between MUC1-CD and ß-catenin is in part responsible for this response (20). Other studies have demonstrated that MUC1-CD functions as a substrate for glycogen synthase 3ß (21), c-Src (22), protein kinase Cδ (23) and c-Abl (12). These findings have indicated that, in contrast to the N-terminal mucin-type ectodomain, MUC1-C transduces signals from the cell membrane to the interior of the cell that confer growth and survival responses.…”

Section: Introductionmentioning

confidence: 99%

Evolution of the human MUC1 oncoprotein

Duraisamy¹,

Kufe²,

Ramasamy³

et al. 2007

Int J Oncol

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Abstract. The mucin (MUC) family consists of secreted and membrane-bound forms. The transmembrane mucin 1 (MUC1) is a heterodimer that is aberrantly overexpressed by diverse human carcinomas and certain hematologic malignancies. The MUC1 N-terminal (MUC1-N) and C-terminal (MUC1-C) subunits are generated by autocleavage within a SEA domain. The MUC1 cytoplasmic domain (MUC1-CD) located downstream of the SEA domain is sufficient for the induction of anchorage-independent growth and tumorigenicity; however, no information is available regarding the origin of these transforming sequences. Previous work demonstrated that, except for the SEA domain, MUC1 has no sequence homology with other membrane-bound mucins. The present results demonstrate that MUC1-CD evolved from repeat regions in the MUC5B secreted mucin. We also show that MUC1 sequences upstream to the SEA domain emerged from MUC5B. These findings indicate that both the MUC1-N and MUC1-C subunits evolved from secreted gel-forming mucins and that the MUC1-CD oncogenic function emerged by diversification after evolution from MUC5B.

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Cell signaling through membrane mucins

et al. 2002

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MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 in the absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds beta-catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia.

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The c-Src Tyrosine Kinase Regulates Signaling of the Human DF3/MUC1 Carcinoma-associated Antigen with GSK3β and β-Catenin

Cited by 214 publications

References 32 publications

MUC1 Initiates Src-CrkL-Rac1/Cdc42–Mediated Actin Cytoskeletal Protrusive Motility after Ligating Intercellular Adhesion Molecule-1

MUC1 Initiates Src-CrkL-Rac1/Cdc42–Mediated Actin Cytoskeletal Protrusive Motility after Ligating Intercellular Adhesion Molecule-1

Evolution of the human MUC1 oncoprotein

Cell signaling through membrane mucins

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