Involvement of p130Cas and p105HEF1, a Novel Cas-like Docking Protein, in a Cytoskeleton-dependent Signaling Pathway Initiated by Ligation of Integrin or Antigen Receptor on Human B Cells

Manié, Serge N.; Beck, Andreas; Astier, Anne; Law, Susan F.; Canty, T.; Hirai, Hisamaru; Druker, Brian J.; Avraham, Hava; Haghayeghi, Nilou; Sattler, Martin; Salgia, Ravi; Griffin, James D.; Golemis, Erica A.; Freedman, Arnold S.

doi:10.1074/jbc.272.7.4230

Cited by 114 publications

(132 citation statements)

References 38 publications

(38 reference statements)

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“…Ligation of ␤1 integrin receptors induces association of CRKL with CBL, HEF1, or CAS. 29,30 CAS (for Crk-associated substrate) was cloned as a major 130 kDa tyrosine phosphorylated protein in response to v-crk transformation. 27 Currently, there are three CAS-related molecules (the 130 kDa protein CAS, the 110 kDa protein HEF1/CAS-L, 67,68 and the 95 kDa protein SIN/EFS 69,70 ).…”

Section: Cas Hef1mentioning

confidence: 99%

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

Sattler

Salgia

1998

Leukemia

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CRKL is a 39 kDa adapter protein, originally cloned in proximity to the BCR gene on chromosome 22, which has a key regulatory role in hematopoietic cells. CRKL has one SH2 and two SH3 domains, with 60% homology to CRK II. CRKL is a prominent substrate of the BCR/ABL oncoprotein in chronic myelogenous leukemia and binds to both BCR/ABL and c-ABL. CRKL has been shown to be tryosine phosphorylated in response to normal hematopoietic growth factor receptor signaling with ligands such as thrombopoietin, erythropoietin or steel factor. Additionally, CRKL is involved in signaling initiated by crosslinking of ␤ integrins, and B cell or T cell receptors. Structurally, the amino-terminal SH3 domain of CRKL has been shown to bind proteins such as C3G, SOS, PI3-K, c-ABL or BCR/ABL. The SH2 domain of CRKL can bind to tyrosine phosphorylated proteins such as CBL, HEF1, CAS or paxillin. This review summarizes the current knowledge on the function of this unique adapter protein in normal hematopoietic and leukemic cell signaling.

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Section: Cas Hef1mentioning

confidence: 99%

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

Sattler

Salgia

1998

Leukemia

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“…Other reported substrates for PTP-PEST in non-lymphoid cells include Cas (Cote et al, 1998;Garton et al, 1996), Pyk2 and Fak (Lyons et al, 2001). Since many of these same proteins are involved also in integrin signaling and assembly of the immunological synapse in lymphocytes (Manie et al, 1997), it seems likely that PTP-PEST may have a major impact on antigen recognition and T cell activation.…”

Section: Introductionmentioning

confidence: 99%

TCR-induced downregulation of protein tyrosine phosphatase PEST augments secondary T cell responses

Arimura

Vang

Tautz

et al. 2008

Molecular Immunology

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We report that the protein tyrosine phosphatase PTP-PEST is expressed in resting human and mouse CD4 + and CD8 + T cells, but not in Jurkat T leukemia cells, and that PTP-PEST protein, but not mRNA, was dramatically down-regulated in CD4 + and CD8 + primary human T cells upon T cell activation. This was also true in mouse CD4 + T cells, but less striking in mouse CD8 + T cells. PTP-PEST reintroduced into Jurkat at levels similar to those in primary human T cells, was a potent inhibitor of TCR-induced transactivation of reporter genes driven by NFAT/AP-1 and NF-κB elements and by the entire IL-2 gene promoter. Introduction of PTP-PEST into previously activated primary human T cells also reduced subsequent IL-2 production by these cells in response to TCR and CD28 stimulation. The inhibitory effect of PTP-PEST was associated with dephosphorylation the Lck kinase at its activation loop site (Y394), reduced early TCR-induced tyrosine phosphorylation, reduced ZAP-70 phosphorylation and inhibition of MAP kinase activation. We propose that PTP-PEST tempers T cell activation by dephosphorylating TCR-proximal signaling molecules, such as Lck, and that down-regulation of PTP-PEST may be a reason for the increased response to TCR triggering of previously activated T cells.

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“…Several reports demonstrated that HEF1 is mainly expressed in lymphoid and epithelial cells [2,3]. It has been implicated in signalling pathways initiated by ligation of integrins or antigen on BCR or TCR [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

Hivert

Pierre

Raingeaud

2009

Biochemical Pharmacology

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Please cite this article as: Hivert V, Pierre J, Raingeaud J, Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Cas family. HEF1 is present at focal adhesions and is involved in integrin signalling mediating cytoskeleton reorganization associated with cell migration, adhesion or apoptosis.HEF1 functions are regulated in part by phosphorylation on tyrosine residues. HEF1 is also phosphorylated on serines/threonines leading to two isoforms refered to as p105 and p115. In most cases, the serine/threonine kinase(s) responsible for HEF1 phosphorylation have not been identified. In the present study, we have investigated HEF1 ser/thr phosphorylation. In the HCT-116 cell line transiently overexpressing Flag-HEF1 we showed that Hesperadin, a synthetic indolinone displaying antiproliferative effect and described as an inhibitor of various kinases including Aurora-B, prevented HEF1 phosphorylation induced by the ser/thr phosphatase PP2A inhibitor : okadaic acid (OA). In addition we showed that conversion of endogenous HEF1 p105 to p115 in HaCaT cells was prevented upon treatment with Hesperadin, resulting in accumulation of p105HEF1. We also identified serine 369 as the target site of phosphorylation by this Hesperadin-inhibited kinase in HCT-116. Finally, we * ManuscriptPage 2 of 37 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 provide evidence that phosphorylation on serine 369 but not phosphorylation on serine 296, triggers HEF1 degradation by the proteasomal machinery. These data suggest that conversion of p105 to p115 results from a ser-369-dependent phosphorylation mediated by an Hesperadin-sensitive kinase and regulates the half-life of HEF1.Keywords: human enhancer of filamentation 1, protein phosphatase 2A, Hesperadin, protein stability.

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Involvement of p130Cas and p105HEF1, a Novel Cas-like Docking Protein, in a Cytoskeleton-dependent Signaling Pathway Initiated by Ligation of Integrin or Antigen Receptor on Human B Cells

Abstract: The Crk-associated substrate p130 Cas (Cas) and the recently described human enhancer of filamentation 1 (HEF1) are two proteins with similar structure (64% amino acid homology), which are thought to act as "docking" molecules in intracellular signaling cascades.

Cited by 114 publications

References 38 publications

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells

TCR-induced downregulation of protein tyrosine phosphatase PEST augments secondary T cell responses

Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

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