Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells
ABSTRACT Semaphorins are multifunctional factors implicated in various developmental processes. Little is known about the intracellular pathways ensuring appropriate signal transduction that encode the diverse functions observed. In this study, we investigated whether mitogen-activated protein kinases (MAPK), which are key elements of signal transduction in eukaryotic cells, were activated during semaphorin 3A (Sema3A)-induced repulsion or apoptosis of neural progenitor cells. We found that selective recruitment of the ERK1/2 pathway occurred during Sema3A-induced neural progenitor cell repulsion, whereas p38 MAPK activation was necessary for induction of apoptosis. Moreover, we provide evidence for the involvement of vascular endothelial growth factor receptor 1 (VEGFR1) in the activation of ERK1/2. Additional experiments performed with native cerebellar progenitors confirmed such a selective recruitment of MAPK during Sema3A-dependent migration or apoptosis. Altogether, our results suggest a model to explain how a single factor can exert different functions for a given cell type by the selective recruitment of intracellular pathways.
Article: A PKC-dependent recruitment of MMP-2 controls semaphorin-3A growth-promoting effect in cortical dendrites.[show abstract] [hide abstract]
ABSTRACT: There is increasing evidence for a crucial role of proteases and metalloproteinases during axon growth and guidance. In this context, we recently described a functional link between the chemoattractive Sema3C and Matrix metalloproteinase 3 (MMP3). Here, we provide data demonstrating the involvement of MMP-2 to trigger the growth-promoting effect of Sema3A in cortical dendrites. The in situ analysis of MMP-2 expression and activity is consistent with a functional growth assay demonstrating in vitro that the pharmacological inhibition of MMP-2 reduces the growth of cortical dendrites in response to Sema3A. Hence, our results suggest that the selective recruitment and activation of MMP-2 in response to Sema3A requires a PKC alpha dependent mechanism. Altogether, we provide a second set of data supporting MMPs as effectors of the growth-promoting effects of semaphorins, and we identify the potential signalling pathway involved.PLoS ONE 02/2009; 4(4):e5099. · 4.09 Impact Factor
Article: The semaphorins.[show abstract] [hide abstract]
ABSTRACT: Semaphorins are secreted, transmembrane, and GPI-linked proteins, defined by cysteine-rich semaphorin protein domains, that have important roles in a variety of tissues. Humans have 20 semaphorins, Drosophila has five, and two are known from DNA viruses; semaphorins are also found in nematodes and crustaceans but not in non-animals. They are grouped into eight classes on the basis of phylogenetic tree analyses and the presence of additional protein motifs. The expression of semaphorins has been described most fully in the nervous system, but they are also present in most, or perhaps all, other tissues. Functionally, semaphorins were initially characterized for their importance in the development of the nervous system and in axonal guidance. More recently, they have been found to be important for the formation and functioning of the cardiovascular, endocrine, gastrointestinal, hepatic, immune, musculoskeletal, renal, reproductive, and respiratory systems. A common theme in the mechanisms of semaphorin function is that they alter the cytoskeleton and the organization of actin filaments and the microtubule network. These effects occur primarily through binding of semaphorins to their receptors, although transmembrane semaphorins also serve as receptors themselves. The best characterized receptors for mediating semaphorin signaling are members of the neuropilin and plexin families of transmembrane proteins. Plexins, in particular, are thought to control many of the functional effects of semaphorins; the molecular mechanisms of semaphorin signaling are still poorly understood, however. Given the importance of semaphorins in a wide range of functions, including neural connectivity, angiogenesis, immunoregulation, and cancer, much remains to be learned about these proteins and their roles in pathology and human disease.Genome biology 02/2006; 7(3):211. · 6.63 Impact Factor
Article: Semaphorins in cancer.[show abstract] [hide abstract]
ABSTRACT: The semaphorins are the products of a large family of genes currently containing more than 30 members. These genes are divided into eight classes of which classes 1, 2 and 8 contain invertebrate and viral semaphorins, while classes 3-7 contain the vertebrate semaphorins. The semaphorins have been implicated in diverse developmental processes such as axon guidance during nervous system development and regulation of cell migration. Plexin receptors function as binding and signal transducing receptors for all semaphorins except for the class-3 semaphorins which bind to neuropilins which subsequently activate signaling through associated plexins. The class-3 semaphorins semaphorin-3B (s3b) and semaphorin-3F (s3f) function additionally as potent inhibitors of tumor development in small cell lung carcinoma. Recent evidence indicates that these semaphorins modulate the adhesive and migratory properties of responsive malignant cells. S3f as well as semaphorin-3A (s3a) were also found to function as inhibitors of angiogenesis, and it was shown that the anti-angiogenic properties of s3f contribute significantly to its anti-tumorigenic properties. In contrast with these inhibitory semaphorins, there is some evidence indicating that semaphorins such as semaphorin-3C (s3c), semaphorin-3E (s3e), semaphorin-4D (s4d), semaphorin-5C (s5c) semaphorin-6A (s6a) and semaphorin-6b (s6b) may contribute to tumorigenesis or to tumor progression. In this review we discuss the semaphorins, their receptors and their signal transduction mechanisms, and evidence linking semaphorins to the control of tumorigenesis and tumor progression.Frontiers in Bioscience 02/2005; 10:751-60. · 3.52 Impact Factor