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Vol. 18, Issue 5, 1621-1633, May 2007

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The Short Arm of Laminin 2 Chain of Laminin-5 (Laminin-332) Binds Syndecan-1 and Regulates Cellular Adhesion and Migration by Suppressing Phosphorylation of Integrin 4 Chain

Takashi Ogawa^*,, Yoshiaki Tsubota^*,, Junko Hashimoto^*,, Yoshinobu Kariya^*,, and Kaoru Miyazaki^*,

*Division of Cell Biology, Kihara Institute for Biological Research, and Graduate School of Integrated Sciences, Yokohama City University, Yokohama 244-0813, Japan; and Kihara Memorial Yokohama Biotechnology Foundation, Yokohama 244-0813, Japan

Submitted September 11, 2006; Revised January 10, 2007; Accepted February 9, 2007
Monitoring Editor: Mark Ginsberg

The proteolytic processing of laminin-5 at the short arm of the 2 chain (2sa) is known to convert this laminin from a cell adhesion type to a motility type. Here, we studied this mechanism by analyzing the functions of 2sa. In some immortalized or tumorigenic human cell lines, a recombinant 2sa, in either soluble or insoluble (coated) form, promoted the adhesion of these cells to the processed laminin-5 (Pr-LN5), and it suppressed their migration stimulated by serum or epidermal growth factor (EGF). 2sa also suppressed EGF-induced tyrosine phosphorylation of integrin 4 and resultant disruption of hemidesmosome-like structures in keratinocytes. 2sa bound to syndecan-1, and this binding, as well as its cell adhesion activity, was blocked by heparin. By analyzing the activities of three different 2sa fragments, the active site of 2sa was localized to the NH₂-terminal EGF-like sequence (domain V or LEa). Suppression of syndecan-1 expression by the RNA interference effectively blocked the activities of domain V capable of promoting cell adhesion and inhibiting the integrin 4 phosphorylation. These results demonstrate that domain V of the 2 chain negatively regulates the integrin 4 phosphorylation, probably through a syndecan-1–mediated signaling, leading to enhanced cell adhesion and suppressed cell motility.

Address correspondence to: Kaoru Miyazaki (miyazaki{at}yokohamacu.ac.jp)

Abbreviations used: 2dV, recombinant 2 protein containing only domain V; 2pf, recombinant 2 protein containing mainly domains V and IV; 2sa, recombinant protein of laminin 2 short arm; BSA, bovine serum albumin; FCS, fetal calf serum; HSPG, heparan sulfate proteoglycan; LN5, laminin-5; mAb, monoclonal antibody; Np-LN5, recombinant laminin-5 with a nonprocessed, mutated 2 chain; Pr-LN5, natural laminin-5 with a processed 2 chain.

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