| Melanoma, a UV inducible tumor of melanocytes, is caused by complex and disordered molecular and genetic pathways. One such pathway involves Plexins, which are transmembrane receptors for axonal growth cone guidance molecules called semaphorins. Plexin B1, the receptor for semaphorin 4D (Sema4D) is recognized as a tumor suppressor protein for melanoma and has been implicated as both tumor promoting and suppressing in several other solid cancers. In melanoma, Plexin B1 suppresses tumorgenesis in part through its ability to repress activation of the oncogenic c-Met (MET) receptor by its ligand hepatocyte growth factor (HGF). MET is a membrane bound receptor tyrosine kinase that is critical for the normal development and growth of melanocytes.;Plexin B1 and its relationship with MET in melanocyte biology was not well defined; however, our lab has discovered that Plexin B1 has a profound role in melanocyte biology. We've shown that Plexin B1 regulates Akt and ERK1/2 phosphorylation, which was attenuated in Plexin B1 knockdown cells. These knockdowns also showed increased apoptosis and decreased proliferation. Sema4D treatment blocked HGF-dependent MET activation and cell migration in melanocytes. In addition, Sema4D rescued MET-dependent suppression of E-cadherin, an essential melanocyte-keratinocyte adhesion molecule. We hypothesized that Plexin B1's negative effect on MET activity is due to inhibitory receptor-receptor association. Our results showed that Plexin B1 and MET are co-localized and that Sema4D enhanced this interaction. This complex, we believe, inhibits oligomerization and MET activation.;In order to better understand the relationship between Plexin B1 and MET in melanocytes, Shp2, a widely expressed non-receptor protein tyrosine phosphatase, was examined. Shp2 mediates several major signaling pathways downstream of tyrosine kinase receptors, including MET. We discovered that Sema4D regulates Shp2 expression at the protein and message levels. In addition, Shp2 is required for HGF-dependent phosphorylation of ERK1/2 and Akt in melanocytes. We applied these results to MET/HGF responsive melanomas and hypothesized that melanoma progression can be attenuated by targeting Shp2. We show that inhibiting Shp2 slows tumor progression in mouse xenograft tumors by increasing apoptosis. Analysis of the Shp2 melanoma transcriptome revealed several genes associated with apoptosis, including the oncomir miR-21. These results suggest that Shp2 may be a viable target for melanoma drug therapy. |
