The SH3 Domain of Bruton's Tyrosine Kinase Interacts with Vav, Sam68 and EWS

Guinamard, Rodolphe; Fougereau, Michel; Seckinger, P

doi:10.1046/j.1365-3083.1997.d01-447.x

Cited by 65 publications

(40 citation statements)

References 58 publications

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“…However, we suggest that Tyr phosphorylation is unlikely to be involved in trans-activation. First, although EWS can associate with several tyrosine kinases (Guinamard et al, 1997;Felsch et al, 1999;Kim et al, 1999) and the EAD contains multiple potential tyrosine kinase interaction sites (Mayer et al, 1992;Songyang et al, 1993;1995), we have been unable to detect Tyr phosphorylation within the N- Figure 4 Role of DHRs in trans-activation by Z33. EAD residues 8 ± 40 present in Z33 are shown at the top and are fused to ATF1 and Zta (not shown).…”

Section: Structure Of the Eadmentioning

confidence: 79%

A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene

Liang

Lee

2001

Oncogene

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Chromosomal fusion of the N-terminal region of the Ewings Sarcoma Oncogene (EWS-activation-domain, EAD) to the DNA-binding domains of a variety of cellular transcription factors produce oncogenic proteins (EWS-fusion proteins (EFPs)) that cause distinct malignancies. In EFPs, the EAD acts as a potent transcriptional activation domain and this ability is repressed in the context of normal, non-tumorigenic, EWS. Trans-activation by the EAD is therefore a speci®c characteristic of EFPs and it is thought that EFPs induce tumorigenesis via improper transcriptional activation of cellular genes. Functional elements required for transcriptional activation are dispersed throughout the EAD, as are thirty-one copies of a Degenerate Hexapeptide Repeat (DHR, consensus SYGQQS). This suggests that the EAD contains a highly reiterated functional element related to DHRs. Here we show that in the context of EWS/ATF1, the EFP that causes malignant melanoma of soft parts, trans-cooperation by small regions of the EAD (*30 residues) results in potent transcriptional activation dependent on the conserved tyrosine residues present in DHRs. These ®ndings provide the ®rst evidence for a role of DHRs in EAD-mediated trans-activation and demonstrate that the EAD represents a novel tyrosine-dependent transcriptional activation domain. Oncogene (2001) 20, 4161 ± 4168.

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Section: Structure Of the Eadmentioning

confidence: 79%

A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene

Liang

Lee

2001

Oncogene

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“…Btk has been suggested to regulate phosphoinositide 3-kinase signaling via PIP5K [5] and may interact with other proteins as an adaptor. Previous studies also indicate that Btk binds to and/or phosphorylates several molecules not necessarily related to PLCc signaling pathways [41][42][43][44][45][46][47][48][49][50][51]. In addition, activation of splenic B cells by CD38 requires Btk but is not affected by the pan-PLCc inhibitor U73122 [52].…”

Section: Discussionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

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“…Studies in T-cells indicate that Sam68 may function as an adaptor linking the TCRcoupled Src family kinases Fyn and Lck to downstream e ectors (Vogel and Fujita, 1995;Fusaki et al, 1997;Lang et al, 1999). Numerous other partnerships with di erent SH2 and SH3 domain-containing signaling molecules have also been documented including: PLCg-1, Grb2, Nck, Jak3, SHP-1, Cbl, Grap (Grb2-like protein), the p21 ras GTPase activating protein, the p85 subunit of PI3-kinase, p47 phox and Tec kinase family Finan et al, 1996;Bunnell et al, 1996;Fusaki et al, 1997;Guinamard et al, 1997;Jabado et al, 1997Jabado et al, , 1998Lawe et al, 1997;Trub et al, 1997;Guitard et al, 1998).…”

Section: Nuclear and Perinuclear Targets Of Srcmentioning

confidence: 99%

Selected glimpses into the activation and function of Src kinase

2000

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Since the discovery of the v-src and c-src genes and their products, much progress has been made in the elucidation of the structure, regulation, localization, and function of the Src protein. Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, di erentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation (i.e. v-Src and some human cancers). Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study. Src associates with cellular membranes, in particular the plasma membrane, and endosomal membranes. Studies indicate that the di erent subcellular localizations of Src could be important for the regulation of speci®c cellular processes such as mitogenesis, cytoskeletal organization, and/or membrane tra cking. This review will discuss the history behind the discovery and initial characterization of Src and the regulatory mechanisms of Src activation, in particular, regulation by modi®cation of the carboxyterminal regulatory tyrosine by phosphatases and kinases. Its focus will then turn to the di erent subcellular localizations of Src and the possible roles of nuclear and perinuclear targets of Src. Finally, a brief section will review some of our present knowledge regarding Src involvement in human cancers. Oncogene (2000) 19, 5620 ± 5635.

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The SH3 Domain of Bruton's Tyrosine Kinase Interacts with Vav, Sam68 and EWS

Cited by 65 publications

References 58 publications

A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene

A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene

Btk and phospholipase Cγ2 can function independently during B cell development

Selected glimpses into the activation and function of Src kinase

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