Roles of Sema4D and Plexin-B1 in tumor progression

Abstract

Sema4D, also known as CD100, is a protein belonging to class IV semaphorin. Its physiologic roles in the immune and nervous systems have been extensively explored. However, the roles of Sema4D have extended beyond these traditionally studied territories. Via interaction with its high affinity receptor Plexin-B1, Sema4D-Plexin-B1 involvement in tumor progression is strongly implied. Here, we critically review and delineate the Sema4D-Plexin-B1 interaction in many facets of tumor progression: tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. We correlate the in vitro and in vivo experimental data with the clinical study outcomes, and present a molecular mechanistic basis accounting for the intriguingly contradicting results from these recent studies.

Figure 1

Interaction of Sema4D and its receptors. Sema4D interacts with its low and high affinity receptors, CD72 and Plexin-B1, respectively to elicit various physiologic responses as well as oncogenesis.

Figure 2

Sema4D-Plexin-B1 signaling pathways in angiogenesis. Sema4D engages Plexin-B1 to induce angiogenesis and tumor angiogenesis via two independent downstream pathways. Plexin-B2 might also play a redundant role in this aspect.

Figure 3

Control of cellular motility by Sema 4D-Plexin-B1 interation via the coopeative mechanism. Coupled with the Met, Ron or ErbB-2 tyrosine kinase receptor at the cellular membrane surface, Sema4D interacts with Plexin-B1 to control cellular motility and invasive growth via Gab1 or Rho-dependant pathways.

Figure 4

Control of cellular motility by Sema 4D-Plexin-B1 interation via the intrinsic mechanism. Decreased intrinsic GAP activity of Plexin-B1 also leads to preferential signaling through the stimulatory R-Ras and Rho-dependant pathways.