It’s the Kinase, Stupid!

Abstract

Semaphorins function as axon guidance molecules in the nervous system and also have effects on other biological processes that depend on cell migration, such as immune responses, morphogenesis, and tumor progression. The semaphorin 4D protein (Sema4D) binds to a receptor known as plexin-B1, which signals through interaction with small guanosine triphosphatases (GTPases) and the tyrosine kinases Met and ErbB-2. In an attempt to explain why it is that activation of plexin-B1 is reported to either stimulate or inhibit cell migration in various cell types, Swiercz et al . took a closer look at the roles of Met and ErbB-2. Treatment of human breast cancer MCF-7 cells (which express ErbB-2 but not Met) with Sema4D caused an increase in migration, whereas similar stimulation of the MDA-MB-468 breast cancer cells (which express Met but not ErbB-2) inhibited migration. Sema4D-induced migration in the MCF-7 cells was blocked if ErbB-2 was depleted with siRNA, whereas siRNA to Met had no effect. In the MDA-MB-468 cells, depletion of Met prevented the inhibition of migration in response to Sema4D, and siRNA to ErB-2 had no effect. If the two kinases were swapped between the two cell lines (by depletion of the endogenous kinase with siRNA and replacement with exogenously expressed Met or Erb-B2), the biological effects of Sema4D were reversed (that is, MCF-7 cells expressing Met and depleted of ErbB2 now showed inhibition of migration in response to Sema4D, and MDA-MB-48 cells expressing ErbB-2 instead of Met showed a Sema4D-induced increase in migration). Thus, the coupling of plexin-B1 to distinct tyrosine kinases can account for the opposite effects of Sema4D in various cell types. The authors note that the differential effects on migration are correlated with opposite effects of Met and Erb-B2 on the activity of the small GTPase RhoA, but other differences in signaling by the two tyrosine kinases may also contribute their distinct biological effects. J. M. Swiercz, T. Worzfeld, S. Offermanns, ErbB-2 and Met reciprocally regulate cellular signaling via plexin-B1. J. Biol. Chem. 283 , 1893-1901 (2008). [Abstract] [Full Text]