Structural basis for semaphorin signalling through the plexin receptor

Nogi, Terukazu; Yasui, Norio; Mihara, Emiko; Matsunaga, Yukiko; Noda, Masanori; Yamashita, Naoya; Toyofuku, Toshihiko; Uchiyama, Susumu; Goshima, Yoshio; Kumanogoh, Atsushi; Takagi, Junichi

doi:10.1038/nature09473

Cited by 149 publications

(229 citation statements)

References 41 publications

Supporting

Mentioning

216

Contrasting

Unclassified

Order By: Relevance

“…of the extracellular regions of Sema4A and sortilin revealed a common b-propeller fold that provides a ligandbinding surface for a number of proteins (Gherardi et al 2004;Willnow et al 2008;Quistgaard et al 2009;Nogi et al 2010). Thus, in our proposed model, Sema4A competes with sortilin to bind prosaposin in endosomes that fuse in response to oxidative stress; complexes containing Sema4A and prosaposin are then sorted to the secretory pathway.…”

Section: Sema4amentioning

confidence: 75%

Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival

Toyofuku

Nojima²,

Ishikawa³

et al. 2012

Genes Dev.

Self Cite

View full text Add to dashboard Cite

Photoreceptor cell death is the hallmark of a group of human inherited retinal degeneration. Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Here, we show that Semaphorin 4A (Sema4A), a member of axonal guidance molecule semaphorin, plays a role in Rab11/FIP2-mediated endosomal sorting in retinal pigment epithelial cells to support photoreceptor function. In response to oxidative stress, Sema4A switches the endosomal sorting of the lysosomal precursor protein prosaposin from the lysosome to the exosomal release, which prevents light-induced photoreceptor apoptosis. In the absence of oxidative stress, Sema4A sorts retinoid-binding proteins with retinoids between the cell surface and endoplasmic reticulum, by which 11-cis-retinal, a chromophore for phototransduction, is regenerated and transported back to photoreceptors. Owing to defects in these processes, Sema4A-deficient mice exhibit marked photoreceptor degeneration. Our findings therefore indicate that Sema4A regulates two distinct endosomal-sorting pathways that are critical for photoreceptor survival and phototransduction during the transition between daylight and darkness.

show abstract

Section: Sema4amentioning

confidence: 75%

Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival

Toyofuku

Nojima²,

Ishikawa³

et al. 2012

Genes Dev.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The co-IP of Sema6A with PlxnA2 was used as positive control, as this interaction has been described previously (Suto et al, 2005(Suto et al, , 2007Toyofuku et al, 2008;Janssen et al, 2010;Nogi et al, 2010). Immunoprecipitation of myc-tagged PlxnA2 ectodomains from conditioned medium was found to pull down both Sema6B-Fc and Sema6A-Fc ectodomains (Fig.…”

Section: Sema6b Interacts With Plxna2mentioning

confidence: 81%

“…Based on its precise temporal and spatial coincidence with axonal midline crossing, the switch from Sema6B-PlxnA2 cis-to trans-interaction constitutes an excellent regulatory mechanism that contributes to and strengthens the previously described mechanisms: the Shh-induced regulation of PKA activity (Parra and Zou, 2010) and the GDNF-mediated and However, axons are not affected by the low levels of repulsive signals (blue diamond) and readily grow towards the ventral midline. Note that we have drawn PlxnA2 (green) arbitrarily as dimer or monomer based on reports on the crystal structures of Sema6A and PlxnA2 (for details see Janssen et al, 2010;Nogi et al, 2010). For simplicity, we omitted neuropilins, which would form complexes with plexins.…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 6B acts as a receptor in post-crossing commissural axon guidance

et al. 2014

View full text Add to dashboard Cite

Semaphorins are a large family of axon guidance molecules that are known primarily as ligands for plexins and neuropilins. Although class-6 semaphorins are transmembrane proteins, they have been implicated as ligands in different aspects of neural development, including neural crest cell migration, axon guidance and cerebellar development. However, the specific spatial and temporal expression of semaphorin 6B (Sema6B) in chick commissural neurons suggested a receptor role in axon guidance at the spinal cord midline. Indeed, in the absence of Sema6B, post-crossing commissural axons lacked an instructive signal directing them rostrally along the contralateral floorplate border, resulting in stalling at the exit site or even caudal turns. Truncated Sema6B lacking the intracellular domain was unable to rescue the loss-of-function phenotype, confirming a receptor function of Sema6B. In support of this, we demonstrate that Sema6B binds to floorplate-derived plexin A2 (PlxnA2) for navigation at the midline, whereas a cis-interaction between PlxnA2 and Sema6B on pre-crossing commissural axons may regulate the responsiveness of axons to floorplate-derived cues.

show abstract

“…Here we provide a definitive physiologic demonstration of catch bond regulation by a semaphorin signaling through a plexin. Despite reports of cross-talk between plexins, the cytoskeleton, and integrins, there is little evidence to support a specific signaling mechanism (43) or uniform conformational change on a semaphorin binding to a plexin (44,45). Because the absence of plexinD1 does not release the activated conformation of β1 integrin but only the constraints on the tight nanoscale membrane clustering, we must conclude that the sema3E-independent function of plexinD1 does not affect the known intracellular dynamics of integrin activation.…”

Section: Discussionmentioning

confidence: 93%

Dynamic control of β1 integrin adhesion by the plexinD1-sema3E axis

Choi

Duke‐Cohan

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Plexins and semaphorins comprise a large family of receptorligand pairs controlling cell guidance in nervous, immune, and vascular systems. How plexin regulation of neurite outgrowth, lymphoid trafficking, and vascular endothelial cell branching is linked to integrin function, central to most directed movement, remains unclear. Here we show that on developing thymocytes, plexinD1 controls surface topology of nanometer-scaled β1 integrin adhesion domains in cis, whereas its ligation by sema3E in trans regulates individual β1 integrin catch bonds. Loss of plexinD1 expression reduces β1 integrin clustering, thereby diminishing avidity, whereas sema3E ligation shortens individual integrin bond lifetimes under force to reduce stability. Consequently, both decreased expression of plexinD1 during developmental progression and a thymic medulla-emanating sema3E gradient enhance thymocyte movement toward the medulla, thus enforcing the orchestrated lymphoid trafficking required for effective immune repertoire selection. Our results demonstrate plexin-tunable molecular features of integrin adhesion with broad implications for many cellular processes.thymocyte development | mechanobiology | integrin activation | autoimmunity | central tolerance I t is well established that plexins and their semaphorin ligands regulate biological processes in multiple physiological domains including axon pathfinding (1, 2), angiogenesis (3), and immunity (4). Although plexins harbor potential for regulating small GTPases that mediate cytoskeletal remodeling, either through a direct cytoplasmic GTPase-activating protein (GAP) domain and Rac/Rho-GTPase binding domain or through sequestration of guanidine nucleotide exchange factor (GEF) proteins to the membrane-proximal cytoplasmic face, there is little consensus on plexin signaling pathways in a complex physiological context (5).While studying the molecular interactions controlling mouse thymocyte development, we identified plexinD1 as a critical mediator for thymocytes destined to mature into T lymphocytes populating the mammalian immune system (6). Plxnd1 encoding plexinD1 is transcriptionally regulated at a key intermediate stage of thymocyte development. Double-negative (DN) thymocytes lacking expression of CD4 and CD8 as well as plexinD1 differentiate in the thymic cortex into largely nondividing CD4 + CD8 + double-positive (DP) thymocytes that display surface αβ T-cell receptors (TCRs) and express plexinD1 (6). Despite being highly mobile (7), DP thymocytes remain sequestered in the cortex in frequent physical association with thymic epithelial cells (TECs), moving toward the thymic medulla via chemokine guidance only subsequent to TCR stimulation by self-derived peptide/MHC complexes (pMHC) that induce CD69 expression and support cell survival, i.e., positive selection (8, 9). CD69 + DP cells differentiate further into CD4 + CD8 − or CD4 − CD8 + singlepositive (SP) thymocytes, translocating to the thymic medulla to complete their maturation (10, 11). While traversing the thymus, immatu...

show abstract

Structural basis for semaphorin signalling through the plexin receptor

Cited by 149 publications

References 41 publications

Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival

Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival

Semaphorin 6B acts as a receptor in post-crossing commissural axon guidance

Dynamic control of β1 integrin adhesion by the plexinD1-sema3E axis

Contact Info

Product

Resources

About