Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis.
Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses. The primary receptors for semaphorins are members of the plexin family. In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins, whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins. Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system. However, the role of plexin-A1 in vivo, and the mechanisms underlying its pleiotropic functions, remain unclear. Here, we generated plexin-A1-deficient (plexin-A1(-/-)) mice and identified its important roles, not only in immune responses, but also in bone homeostasis. Furthermore, we show that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. These findings reveal an unexpected role for plexin-A1 and present a novel signalling mechanism for exerting the pleiotropic functions of semaphorins.
Takegahara
Noriko
N
Department of Molecular Immunology and CREST program of JST, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Takamatsu
Hyota
H
Toyofuku
Toshihiko
T
Tsujimura
Tohru
T
Okuno
Tatsusada
T
Yukawa
Kazunori
K
Mizui
Masayuki
M
Yamamoto
Midori
M
Prasad
Durbaka V R
DV
Suzuki
Kazuhiro
K
Ishii
Masaru
M
Terai
Kenta
K
Moriya
Masayuki
M
Nakatsuji
Yuji
Y
Sakoda
Saburo
S
Sato
Shintaro
S
Akira
Shizuo
S
Takeda
Kiyoshi
K
Inui
Masanori
M
Takai
Toshiyuki
T
Ikawa
Masahito
M
Okabe
Masaru
M
Kumanogoh
Atsushi
A
Kikutani
Hitoshi
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001842:Bone and Bones / Q000502:physiology*; D006706:Homeostasis; D007109:Immunity; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; C484963:Tyrobp protein, mouse