alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine, a heparin-binding growth factor.
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 beta1 integrin in midkine-binding proteins from 13-day-old mouse embryos. beta1-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 alpha4 and alpha6. Purified alpha4beta1- and alpha6beta1-integrins bound midkine. Anti-alpha4 antibody inhibited the midkine-dependent migration of osteoblastic cells, and anti-alpha6 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 alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine. We observed that the low-density-lipoprotein-receptor-related-protein-6 ectodomain was immunoprecipitated with alpha6beta1-integrin and alpha4beta1-integrin. The low-density-lipoprotein-receptor-related-protein-6 ectodomain was also immunoprecipitated with receptor-type protein tyrosine phosphatase zeta. alpha4beta1- and alpha6beta1-Integrins are expected to co-operate with other midkine receptors, possibly in a multimolecular complex that contains other midkine receptors.
Department of Biochemistry and Division of Disease Models, Center for Neural Disease and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Hisako
H
Muramatsu
Peng
P
Zou
Hiromichi
H
Suzuki
Yoshihiro
Y
Oda
Guo-Yun
GY
Chen
Nahoko
N
Sakaguchi
Sadatoshi
S
Sakuma
Nobuaki
N
Maeda
Masaharu
M
Noda
Yoshikazu
Y
Takada
Takashi
T
Muramatsu
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D004625:Embryo, Nonmammalian / Q000378:metabolism; D017353:Gene Deletion; D006133:Growth Substances / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D047468:Immunoprecipitation; D039041:Integrin alpha4beta1 / Q000502:physiology*; D039121:Integrin alpha6beta1 / Q000502:physiology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D051379:Mice; D000078792:Midkine; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D016207:Cytokines; D003598:Cytoskeletal Proteins; D006133:Growth Substances; D039041:Integrin alpha4beta1; D039121:Integrin alpha6beta1; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; C496063:Pxn protein, rat; D000078792:Midkine; D014443:Tyrosine; D006493:Heparin; D017027:Protein Tyrosine Phosphatases; C516896:Ptprz1 protein, mouse; C516897:Ptprz1 protein, rat; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5