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JCS ePress online publication date 5 Oct 2004
doi: 10.1242/jcs.01423

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Research Article

{alpha}4{beta}1- and {alpha}6{beta}1-integrins are functional receptors for midkine, a heparin-binding growth factor


Hisako Muramatsu, Peng Zou, Hiromichi Suzuki, Yoshihiro Oda, Guo-Yun Chen, Nahoko Sakaguchi, Sadatoshi Sakuma, Nobuaki Maeda, Masaharu Noda, Yoshikazu Takada, and Takashi Muramatsu*
* Author for correspondence (e-mail: tmurama{at}med.nagoya-u.ac.jp)

Midkine is a heparin-binding growth factor that promotes the growth, survival, migration and differentiation of various target cells. So far, receptor-type protein tyrosine phosphatase {zeta}, low-density-lipoprotein-receptor-related protein and anaplastic lymphoma kinase have been identified as receptors for midkine. We found {beta}1 integrin in midkine-binding proteins from 13-day-old mouse embryos. {beta}1-Integrin bound to a midkine-agarose column and was eluted mostly with EDTA. Further study revealed that the {alpha}-subunits capable of binding to midkine were {alpha}4 and {alpha}6. Purified {alpha}4{beta}1- and {alpha}6{beta}1-integrins bound midkine. Anti-{alpha}4 antibody inhibited the midkine-dependent migration of osteoblastic cells, and anti-{alpha}6 antibody inhibited the midkine-dependent neurite outgrowth of embryonic neurons. After midkine treatment, tyrosine phosphorylation of paxillin, an integrin-associated molecule, was transiently increased in osteoblastic cells. Therefore, we concluded that {alpha}4{beta}1- and {alpha}6{beta}1-integrins are functional receptors for midkine. We observed that the low-density-lipoprotein-receptor-related-protein-6 ectodomain was immunoprecipitated with {alpha}6{beta}1-integrin and {alpha}4{beta}1-integrin. The low-density-lipoprotein-receptor-related-protein-6 ectodomain was also immunoprecipitated with receptor-type protein tyrosine phosphatase {zeta}. {alpha}4{beta}1- and {alpha}6{beta}1-Integrins are expected to co-operate with other midkine receptors, possibly in a multimolecular complex that contains other midkine receptors.
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