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Vol. 17, Issue 6, 2839-2852, June 2006

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A Discoidin Domain Receptor 1/SHP-2 Signaling Complex Inhibits 21-Integrin–mediated Signal Transducers and Activators of Transcription 1/3 Activation and Cell Migration

Chau-Zen Wang^*, Hsiao-Wen Su^*, Yu-Chih Hsu, Meng-Ru Shen, and Ming-Jer Tang^*,,

*Institute of Basic Medical Sciences, Departments of Physiology and Pharmacology, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University Medical College, Tainan 701, Taiwan

Submitted November 21, 2005; Revised March 24, 2006; Accepted March 30, 2006
Monitoring Editor: Carl-Henrik Heldin

Regulation of cell migration is an important step for the development of branching tubule morphogenesis in collagen gel. Here, we showed that discoidin domain receptor (DDR) 1a/b inhibited collagen-induced tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 1/3 and cell migration triggered by 21-integrin. Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2. Expression of catalytically inactive SHP-2 in DDR1-transfected cells restored the tyrosine phosphorylation of Stat3 and cell migration. We demonstrated that the Src homology-2 (SH2)-SH2 and phosphotyrosyl phosphatase (PTP) domains of SHP-2 were responsible for interaction with DDR1 and that both tyrosine phosphorylation sites 703 and 796 of DDR1 were essential for it to bind with SHP-2. Mutation of tyrosine 703 or 796 of DDR1 abolished the ability of DDR1 to inhibit the tyrosine phosphorylation of Stat1 and Stat3 and restored collagen-induced cell migration and hepatocyte growth factor-induced branching tubulogenesis in collagen gel. Together, these results demonstrate that SHP-2 is required for the DDR1-induced suppression of Stat1 and Stat3 tyrosine phosphorylation, cell migration, and branching tubulogenesis.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Ming-Jer Tang ( mjtang1{at}mail.ncku.edu.tw)

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