Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-Met.
Melanoma arises through complex genetic and epigenetic changes, resulting in uncontrolled proliferation, invasion, and metastatic disease. Semaphorins regulate axon guidance through interaction with their receptors, plexins and neuropilins. Plexin B1, the semaphorin 4D receptor, activates oncogenic receptors c-Met and ErbB-2 in several cell types, suggesting it promotes tumor growth through stimulation of these receptors. A study by Argast et al. has shown that plexin B1 is a tumor-suppressor protein for melanoma metastasis in a mouse model. In this report, we show that plexin B1 is lost in metastatic and deeply invasive melanoma in patient samples in vivo. Unexpectedly, introduction of plexin B1 into human melanoma cell lines suppressed, rather than activated, the oncogenic receptor, c-Met, by its ligand hepatocyte growth factor (HGF). Plexin B1 also activated Akt in melanoma. Plexin B1 significantly abrogated cell migration in response to HGF but rendered cells resistant to apoptosis by cisplatin. Plexin B1 is predicted to function as a classic tumor-suppressor protein in melanoma, in part through suppression of c-Met signaling and c-Met-dependent migration. However, because plexin B1 activates Akt, a multifunctional protein involved in tumor progression in several cancers, plexin B1 may function as a tumor promoter in melanomas not driven by c-Met activation.
Stevens
Laurel
L
Department of Dermatology, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14618, USA.
McClelland
Lindy
L
Fricke
Alex
A
Williamson
Magali
M
Kuo
Ihsin
I
Scott
Glynis
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D012878:Skin Neoplasms / Q000503:physiopathology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D000970:Antineoplastic Agents; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin