Showing papers by "Katherine A. Siminovitch published in 2003"
TL;DR: It is suggested that PSTPIP1 acts downstream of CD2/CD2AP to link CD2 engagement to the WASp-evoked actin polymerization required for synapse formation and T cell activation.
197 citations
TL;DR: It is demonstrated that mice deficient in SHIP1, SHP-1, and Btk respond to the ameliorating effects of IVIg with the same kinetics as control mice, indicating that IVIGmediated inhibitory pathways operating via monocyte FcgammaRIIB may involve a transmembrane signaling pathway different from that of B cells.
124 citations
TL;DR: It is suggested that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity, and both the basal and NGF-regulated level of Trk A activity in neurons are controlled.
Abstract: Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity.
98 citations
TL;DR: Further dissection of the functional and biochemical properties of WASp represents a promising avenue towards defining the molecular mechanisms that convey TCR stimulatory signals to the actin cytoskeleton and integrate cytoskeletal and other signaling systems so as to evoke a biological response.
Abstract: The Wiskott-Aldrich syndrome protein (WASp) has emerged as a central player in the regulation of actin remodeling in T cells. The unique domain structure of WASp and other WASp family members enables these proteins to associate with a myriad of signaling effectors and to thereby regulate the coupling of T cell antigen receptor (TCR) engagement to both cytoskeletal rearrangement and transcriptional activation. This review focuses on these biochemical properties of WASp and also on the mechanisms whereby WASp interactions with its cognate ligands influence T cell activation. Because of its capacity to shift intracellular location and thereby dictate both the timing and the spatial distribution of actin polymerization following cell stimulation, WASp is well positioned to play major regulatory roles in directing a wide range of cellular processes and signaling pathways. Further dissection of the functional and biochemical properties of WASp therefore represents a promising avenue towards defining the molecular mechanisms that convey TCR stimulatory signals to the actin cytoskeleton and integrate cytoskeletal and other signaling systems so as to evoke a biological response.
80 citations
TL;DR: It is demonstrated that SHP-2, a protein tyrosine phosphatase present in focal adhesions, modulates IL-1-induced ERK activation and the transient actin stress fiber disorganization that occurs followingIL-1 treatment in human gingival fibroblasts.
42 citations
Journal Article•
TL;DR: The data provide no evidence to support an association between CARD15 and WG, and no SNP were present in the WG patients at significantly different frequencies than the control population.
Abstract: OBJECTIVE: Polymorphisms and mutations in the NOD2/CARD15 gene have been reported to increase susceptibility to Crohn9s disease (CD) and the rare Blau syndrome, respectively. Both conditions are characterized by granuloma formation. We assessed the influence of variants in the CARD15 gene in another disorder characterized by granuloma, Wegener9s granulomatosis (WG). METHODS: Direct DNA sequencing of the CARD15 gene was performed on 25 patients with WG, and an additional 73 patients were genotyped for the 3 CD associated variants, R702W, G908R, and fs1007. RESULTS: In the WG patients, 10 previously reported single nucleotide polymorphisms (SNP) were identified. No SNP were present in the WG patients at significantly different frequencies than the control population. CONCLUSION: Our data provide no evidence to support an association between CARD15 and WG.
26 citations
Journal Article•
TL;DR: Current information on the genetics of IBD is summarized, emphasizing the discovery of CARD15 variants as susceptibility alleles for Crohn's disease and the impact of this discovery on patient care and in delineating pathogenesis of this complex disease.
Abstract: Maladies intestinales inflammatoires (MII), la maladie de Crohn et la colite ulcereuse ont une etiologie multifactorielle, mais il y a longtemps que l'on reconnait le role de cause a effet important de facteurs genetiques. Des progres recents des technologies genetiques ont rendu possible la dissection des genes a l'origine de maladies courantes, ce qui permet de commencer a comprendre les facteurs hereditaires qui predisposent aux MII. Dans cette etude, nous resumons l'information courante sur les caracteristiques genetiques des MII en mettant l'accent sur la decouverte des variantes CARD15 comme alleles de la vulnerabilite a la maladie de Crohn, ainsi que sur l'impact de cette decouverte sur les soins aux patients et la definition de la pathogenese de cette maladie complexe.
17 citations
10 citations