Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive

Franco, Mélanie; Tamagnone, Luca

doi:10.1038/embor.2008.139

Cited by 69 publications

(64 citation statements)

References 52 publications

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“…However, α2-chn's known association with tyrosine kinase receptors (20) may suggest the involvement of an additional signaling component(s). As α2-chn is required for OMN responses to CXCL12 and HGF, this raises the possibility that PlexinAs might associate with the HGF receptor Met, as has been shown in some contexts for PlexinBs (21). Therefore, the in vivo phenotypes resulting from α2-chn knockdown may represent a composite of loss of responsiveness to Sema3s and CXCL12/HGF.…”

Section: Sema3a and Sema3c Act Via Plexinas To Orchestrate Ocular Motormentioning

confidence: 99%

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Ferrario

Baskaran

Clark

et al. 2012

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

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Eye movements depend on correct patterns of connectivity between cranial motor axons and the extraocular muscles. Despite the clinical importance of the ocular motor system, little is known of the molecular mechanisms underlying its development. We have recently shown that mutations in the Chimaerin-1 gene encoding the signaling protein α2-chimaerin (α2-chn) perturb axon guidance in the ocular motor system and lead to the human eye movement disorder, Duane retraction syndrome (DRS). The axon guidance cues that lie upstream of α2-chn are unknown; here we identify candidates to be the Semaphorins (Sema) 3A and 3C, acting via the PlexinA receptors. Sema3A/C are expressed in and around the developing extraocular muscles and cause growth cone collapse of oculomotor neurons in vitro. Furthermore, RNAi knockdown of α2-chn or PlexinAs in oculomotor neurons abrogates Sema3A/C-dependent growth cone collapse. In vivo knockdown of endogenous PlexinAs or α2-chn function results in stereotypical oculomotor axon guidance defects, which are reminiscent of DRS, whereas expression of α2-chn gain-of-function constructs can rescue PlexinA loss of function. These data suggest that α2-chn mediates Sema3-PlexinA repellent signaling. We further show that α2-chn is required for oculomotor neurons to respond to CXCL12 and hepatocyte growth factor (HGF), which are growth promoting and chemoattractant during oculomotor axon guidance. α2-chn is therefore a potential integrator of different types of guidance information to orchestrate ocular motor pathfinding. DRS phenotypes can result from incorrect regulation of this signaling pathway.

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Section: Sema3a and Sema3c Act Via Plexinas To Orchestrate Ocular Motormentioning

confidence: 99%

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Ferrario

Baskaran

Clark

et al. 2012

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

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“…(17,39,40). Thus, it is likely that the function of Plexin-B1 is context dependent and that Plexin-B1 may have different effects when coexpressed with particular sets of signaling partners in certain cancer types (41).…”

Section: Figurementioning

confidence: 99%

ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

Worzfeld¹,

Swiercz²,

Looso³

et al. 2012

J. Clin. Invest.

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Diagnosis of metastatic breast cancer is associated with a very poor prognosis. New therapeutic targets are urgently needed, but their development is hampered by a lack of understanding of the mechanisms leading to tumor metastasis. Exemplifying this is the fact that the approximately 30% of all breast cancers overexpressing the receptor tyrosine kinase ErbB-2 are characterized by high metastatic potential and poor prognosis, but the signaling events downstream of ErbB-2 that drive cancer cell invasion and metastasis remain incompletely understood. Here we show that overexpression of ErbB-2 in human breast cancer cell lines leads to phosphorylation and activation of the semaphorin receptor Plexin-B1. This was required for ErbB-2-dependent activation of the pro-metastatic small GTPases RhoA and RhoC and promoted invasive behavior of human breast cancer cells. In a mouse model of ErbB-2-overexpressing breast cancer, ablation of the gene encoding Plexin-B1 strongly reduced the occurrence of metastases. Moreover, in human patients with ErbB-2-overexpressing breast cancer, low levels of Plexin-B1 expression correlated with good prognosis. Our data suggest that Plexin-B1 represents a new candidate therapeutic target for treating patients with ErbB-2-positive breast cancer. IntroductionMetastatic breast cancer remains essentially incurable, demonstrating the critical need for the understanding of the molecular determinants of breast cancer cell invasion and metastasis. The receptor tyrosine kinase ErbB-2 is overexpressed in about 30% of all breast cancers, and ErbB-2-overexpressing tumors are characterized by high metastatic potential and poor prognosis (1, 2). Several signaling proteins and pathways have been reported to contribute to the metastatic potential of ErbB-2-overexpressing breast cancers (3-5). These include transmembrane proteins such as integrins and EphA2 (6, 7), as well as cytosolic signaling pathways such as those mediated by Ras, Src, or the PI3K/Akt pathway (8-12). However, despite considerable progress, the signaling events mediating cancer cell invasion and metastasis in ErbB-2-overexpressing tumors are still incompletely understood, and therapeutic options for the treatment of ErbB-2-overexpressing breast cancers remain insufficient. Therefore, a better understanding of the molecular mechanisms driving ErbB-2-dependent metastasis is required to develop more effective treatments for this aggressive type of breast cancer.Plexin-B1 belongs to a family of transmembrane receptors that mediate the cellular effects of semaphorins (13). While plexins were described in the context of axon guidance, several recent studies have established them as regulators of organogenesis, the immune system, and cancer (14-16). Plexin-B1 has been shown to interact with ErbB-2 (17). Binding of the Plexin-B1 ligand semaphorin 4D (Sema4D) to Plexin-B1 stimulates the kinase activity of ErbB-2, which leads to phosphorylation of Plexin-B1 at two specific tyrosine residues (18,19). This regulation of ErbB-2 activity via Plexin-B...

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“…Plexins are pivotal players in this scenario, whereas a putative signaling function of the NPs (beyond their essential role as binding platforms) is currently controversial. Although plexins do not carry an intrinsic kinase activity, they can trigger the activation of plexin-associated receptortype and nonreceptor-type tyrosine kinases (for a review, see Franco and Tamagnone, 2008). By activating plexin-associated kinases and the intrinsic GAP activity of plexins (see below), semaphorin binding can regulate cytoskeletal dynamics, integrin functions, cell adhesion and migration.…”

Section: Sema6dmentioning

confidence: 99%

Semaphorin signaling in cancer cells and in cells of the tumor microenvironment – two sides of a coin

Capparuccia

Tamagnone

2009

Journal of Cell Science

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173

154

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Journal of Cell Science 1724 including cell-adhesion molecule L1 (Castellani and Rougon, 2002) and the receptor tyrosine kinases (RTKs) VEGFR2 (Toyofuku et al., 2004), erythroblastic leukemia viral oncogene homolog 2 (ErbB2) (Swiercz et al., 2004), off-track kinase (OTK) (Winberg et al., 2001) and Met (also known as HGFR) (Giordano et al., 2002). In the immune system, CD72 and Tim2 (T-cell immunoglobulin and mucin domain-containing protein 2) were found to interact functionally (although with low affinity) with the transmembrane semaphorins SEMA4D and SEMA4A, respectively (Kumanogoh et al., 2002;Kumanogoh et al., 2000). Recently, other ligands for NPs have also been described, including fibroblast growth factor 2 (FGF2) (West et al., 2005), hepatocyte growth factor (HGF) (Sulpice et al., 2008) and galectin-1 (Gal-1) (Hsieh et al., 2008). In addition, NPs were recently observed to form complexes with additional cell-surface receptors, including Met (Matsushita et al., 2007), β1 integrin (Fukasawa et al., 2007) and transforming growth factor-β1 (TGF-β1) (Glinka and Prud'homme, 2008) (for reviews see Neufeld and Kessler, 2008;Pellet-Many et al., 2008).In addition to their function in a range of basic cellular processes, recent studies have shown that semaphorin-mediated signals might also play important regulatory functions in cancer . On one side, tumor progression and metastatic dissemination depend on intrinsic properties of cancer cells, such as survival, self-renewal and the ability to migrate and overcome tissue barriers (invasiveness). On the other side, the tumor stroma -which includes endothelial cells, fibroblasts and cells of the immune system -is engaged in active molecular crosstalk with cancer cells. For example, blood-and lymph-vessel angiogenesis, together with inflammatory and immunosuppressive responses, further promotes cancer-cell survival, migration and invasion, as well as initiation of the metastatic cascade. In this Commentary, we review the current knowledge on the emerging role of semaphorin signals in controlling these 'two sides of a coin' -that is, the tumor-cell intrinsic alterations, and the crosstalk between cancer cells and other cells of the tumor microenvironment. In addition, the implications of semaphorin signaling in tumor progression will be discussed. . Of the vertebrate semaphorins, those in classes 4, 5 and 6 are transmembrane proteins, whereas those in class 7 are membrane-anchored via glycophosphatidylinositol (GPI). Class-3 secreted semaphorins have C-terminal basic-charged sequences, which are required for binding to neuropilins. Several class-3 semaphorins and SEMA4D have been shown to undergo regulatory cleavage by furins or metalloproteases. Class-5 semaphorins are distinguished by thrombospondin repeats. Several semaphorins also contain immunoglobulin-like domains. (B) Neuropilins are transmembrane receptors that are characterized by two complement-like (CUB) domains (also called the a1 and a2 domains), two FV/FVIII coagulation factor-like domains (also called the...

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Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive

Cited by 69 publications

References 52 publications

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis

Semaphorin signaling in cancer cells and in cells of the tumor microenvironment – two sides of a coin

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