Xin Zhang, M.D., Ph.D., Assistant Professor
 Department of Medicine

Cell adhesion and cell migration play important roles in variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remodeling, and inflammation. Our laboratory aims to understand the molecules involved in cell adhesion and cell migration and the ways in which they control adhesion and migration of cells in both physiological and pathological processes. Integrin is a major family of adhesion proteins and essential for both cell adhesiveness and cell motility. To understand the molecular mechanism of integrin-mediated cell adhesion and cell migration, the research in our lab is being focused on the roles of integrin-associated proteins in the integrin-dependent biological events such as cancer invasion, metastasis, and angiogenesis. We recently identified a novel protein ICAP-1 that associates with the cytoplasmic domain of b1 integrin and found that ICAP-1 regulates cell movement. ICAP-1 is a ubiquitously expressed intracellular phosphoprotein and contains a PH domain and multiple sites that are phosphorylated by several important signaling enzymes such as PKC, PKA and CamKII. Future study will be directed to the functional analysis of these structural motifs of ICAP-1 in cell adhesion, migration, and integrin signaling. In parallel, we also study the tetraspanin protein that associated with the extracellular domain of b1 integrin. One of the tetraspanins, KAI1/CD82, has been identified as a cancer metastasis suppressor. Metastatic or invasive cancer is usually accompanied with the loss of KAI1/CD82 expression. The mechanism of KAI1/CD82-mediated inhibition of cancer invasion and metastasis remains unclear. We have identified that the FAK-Src-p130 CAS/CrkII-Rac pathway was important for the KAI1/CD82-mediated suppression of cell motility and invasiveness in prostate cancer. During the KAI1/CD82 study, we discovered a novel transmembrane protein that physically associated with tetraspanins and belonged to the immunoglobulin superfamily (IgSF). This IgSF protein, called EWI2/PGRL/KASP, directly regulates cell motility and is likely to be important for KAI1/CD82’s inhibitory activity. These findings will provide mechanistic insight into the cancer metastasis suppression mediated by KAI1/CD82.

Recent Publications

Zhang XA, He B, Zhou B and Liu L. Requirement of p130CAS-Crk coupling in KAI1/CD82-mediated suppression of cell migration. J Biol Chem 278:27319-27328, 2003.

Zhang XA, Lane WS, Charrin S, Rubinstein E and Liu L. EWI2/PGRL Associates with the Metastasis Suppressor KAI1/CD82 and Inhibits the Migration of Prostate Cancer Cells. Cancer Research 63:2665-2674, 2003.

Zhang XA., Kazarov AR, Yang X, Bontrager AL, Stipp CS and Hemler ME. Function of the tetraspanin CD151-a6b1 integrin complex during cellular morphogenesis. Mol Biol Cell 13:1-11, 2002.

Zhang XA, Bontrager AL and Hemler ME. Transmembrane 4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific b1 integrins. J Biol Chem 276:25005-25013, 2001.

Zhang, XA, Bontrager AL, Bazzoni G, Kraeft SK, Stipp CS, Chen LB and Hemler ME. Phosphorylation of a conserved integrin a3 chain QPSXXE motif regulates signaling, motility, and cytoskeletal engagement. Mol Biol Cell 12:351-365, 2001.

Zhang XA and Hemler ME. Interaction of the integrin b1 cytoplasmic domain with ICAP protein. J Biol Chem 274:11-19, 1999.

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