Editors' ChoicePLEXINS

Semaphorins Signal Through an ITAM

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Science's STKE  13 Jun 2006:
Vol. 2006, Issue 339, pp. tw200
DOI: 10.1126/stke.3392006tw200

Semaphorins, which have important roles in development, signal through their receptors, the plexins. Plexin-A1 is a promiscuous molecule that is known to interact with neuropilins to mediate axon guidance signaling and with receptor tyrosine kinases to mediate endocardial cell migration. Now Takegahara et al. show that plexin-A1 also interacts with Trem-2, which is coupled to DAP-12, a protein with an ITAM (immunoreceptor tyrosine-based activation motif) that activates nonreceptor tyrosine kinases. Plexin-A1 knockout mice showed increased bone mass, due to decreased osteoclast activity, and defective activation of T cells by dendritic cells. Sema6D is a semaphorin expressed by T cells, and Takegahara et al. show that it is also expressed by osteoclasts. Application of soluble Sema6D stimulated osteoclast differentiation, and exposure of dendritic cells to soluble Sema6D stimulated production of interleukin 12 and the abundance of major histocompatibility complex II--responses that were lacking in the plexin-A1-deficient cells. Trem-2 was identified in a screen for proteins that interacted with plexin-A1 and were common to both dendritic cells and osteoclasts. Trem-2 also interacts with the ITAM protein DAP-12, and all three proteins coimmunoprecipitated in samples from dendritic cells or from Cos7 cells transfected to coexpress the proteins. DAP12–/– mice exhibit similar deficiencies in dendritic cell function and osteoclast differentiation as do the plexinA1–/– mice. Thus, the pathways by which plexin-A1 can mediate signaling now extend to coupling to ITAM-based mechanisms.

N. Takegahara, H. Takamatsu, T. Toyofuku, T. Tsujimura, T. Okuno, K. Yukawa, M. Mizui, M. Yamamoto, D. V. R. Prasad, K. Suzuki, M. Ishii, K. Terai, M. Moriya, Y. Nakatsuji, S. Sakoda, S. Sato, S. Akira, K. Takeda, M. Inui, T. Takai, M. Ikawa, M. Okabe, A. Kumanogoh, H. Kikutani, Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat. Cell Biol. 8, 615-622 (2006). [PubMed]

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