Physiological signals and oncogenesis mediated through Crk family adapter proteins

Feller, Stephan M.; Posern, Guido; Voß, Jan H.; Kardinal, Christian; Sakkab, Dima; Zheng, Jie; Knudsen, Beatrice S.

doi:10.1002/(sici)1097-4652(199812)177:4<535::aid-jcp5>3.0.co;2-e

Cited by 129 publications

(60 citation statements)

References 154 publications

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“…20 Our hypothesis is that Rap1 could be activated in a similar manner in PV RBCs, HEL, and BaF3 JAK2V617F cells. Consistent with this hypothesis, Feller et al and Chin et al showed that Rap1 was activated by C3G and a member of the Crk family, CrkL, that is predominantly expressed in hematopoietic cells 36 and phosphorylated in response to stimulation with Epo or IL-3. 37 In their study, Arai et al showed that adhesion of the 32D hematopoietic cell line was activated by Epo or IL-3 through the activation of the C3G/CrkL complex, Rap1, and ␤ 1 integrins.…”

Section: Discussionmentioning

confidence: 76%

JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway

Grandis

Cambot

Wautier

et al. 2013

Blood

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Key Points• In polycythemia vera RBCs, JAK2V617F is able to activate an adhesion molecule through a Rap1/Akt pathway, despite the absence of EpoR.• In polycythemia vera, the abnormal adhesion of RBCs to laminin is due to the phosphorylation of Lu/BCAM by a JAK2V617F/Rap1/Akt pathway.Polycythemia vera (PV) is characterized by an increased RBC mass, spontaneous erythroid colony formation, and the JAK2V617F mutation. PV is associated with a high risk of mesenteric and cerebral thrombosis. PV RBC adhesion to endothelial laminin is increased and mediated by phosphorylated erythroid Lu/BCAM. In the present work, we investigated the mechanism responsible for Lu/BCAM phosphorylation in the presence of JAK2V617F using HEL and BaF3 cell lines as well as RBCs from patients with PV. High levels of Rap1-GTP were found in HEL and BaF3 cells expressing JAK2V617F compared with BaF3 cells with wild-type JAK2. This finding was associated with increased Akt activity, Lu/BCAM phosphorylation, and cell adhesion to laminin that were inhibited by the dominant-negative Rap1S17N or by the specific Rap1 inhibitor GGTI-298. Surprisingly, knocking-down EpoR in HEL cells did not alter Akt activity or cell adhesion to laminin. Our findings reveal a novel EpoR-independent IntroductionPolycythemia vera (PV) is the most common myeloproliferative neoplasm. 1 It is characterized by erythropoietin-independent erythroid colony formation in vitro, which is associated with somatic gain-of-function mutations in the gene encoding the tyrosine kinase JAK2. [2][3][4][5] The most frequent mutation is a substitution from valine to phenylalanine at position 617, which renders JAK2 constitutively active, leading to uncontrolled cell proliferation in the erythroid lineage and resulting in increased red cell mass. Patients with PV exhibit increased platelet and leukocyte counts and have a high risk of thrombosis, which is considered a major cause of mortality and morbidity in this disease. 6 In a previous work, we showed that PV RBCs were abnormally adherent to endothelial cells because of the interaction between erythroid Lutheran/basal cell-adhesion molecule (Lu/BCAM) and endothelial laminin. 7 Lu/BCAM is an adhesion protein of the immunoglobulin superfamily with a large tissue distribution. 8,9 It is the unique erythroid receptor of laminin ␣5 chain, constituent of laminin 511/521 isoforms, and a major component of the extracellular matrix. 10,11 Lu/BCAM is expressed as 2 isoforms of 85 and 78 kDa, named Lu and Lu(v13), respectively. 9,10 The 2 isoforms differ only by the length of their cytoplasmic domain, which is composed of 19 a.a. for Lu(v13) and 59 a.a. for Lu. The extra 40 a.a. of Lu comprise phosphorylated serines, 12 which have been shown to play a critical role in Lu/BCAM-mediated RBC adhesion to laminin in sickle cell disease. 13,14 We showed in our previous work that PV RBC adhesion to laminin was associated with Lu/BCAM hyperphosphorylation. Lu/BCAM phosphorylation also was strongly increased in a K562 cell line coexpressing Lu and JAK2V617F, ...

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Section: Discussionmentioning

confidence: 76%

JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway

Grandis

Cambot

Wautier

et al. 2013

Blood

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“…CrkL itself is also inducibly phosphorylated on tyrosine residues [7,11,12]. The N-terminal SH3 domain of CrkL has been reported to interact with the guanine nucleotide exchange factors C3G and Sos, the kinases Abl and hematopoietic progenitor kinase 1 (HPK1), DOCK180, and Wiskott-Aldrich syndrome protein (WASP) [3, [13][14][15][16][17][18]. CrkL is expressed at high levels in hematopoietic cells [19] and has been linked to signaling via the T cell receptor (TCR), the B cell receptor, CD2, and integrins, as well as receptors for the cytokines IL-2, IL-3, IL-5, erythropoietin, thrombopoietin, IFN- § , IFN-+ , hepatocyte growth factor (HGF), and § -chemokines [10,[20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

T cell development and function in CrkL‐deficient mice

et al. 2003

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The adapter protein CrkL has been implicated in multiple signal transduction pathways in hematopoietic cells. In T lymphocytes, the recruitment of CrkL-C3G complexes has been correlated with hyporesponsiveness, implicating CrkL as a potential negative regulator. To test this hypothesis we examined T cell activation in CrkL-deficient mice. The CrkL -/-genotype was partially embryonic lethal. In viable CrkL -/-mice, peripheral blood counts were normal. The thymus from CrkL -/-mice had 40% fewer cells compared to littermates, but the proportion of thymocyte subsets was comparable. There was no discernable alteration in T cell function as reflected by T cell numbers, expression of memory markers, IL-2 production, proliferation, and differentiation into Th1/Th2 phenotypes. Immunization induced comparable levels of IgG2a and IgG1 antibodies. Chimeric mice, generated by transfer of CrkL -/-fetal liver cells into irradiated RAG2-/-recipients, also showed normal T cell function, arguing against selection via partial embryonic lethality. Our results indicate that CrkL is not absolutely required for T cell development or function, and argue against it being an essential component of a negative regulatory pathway in TCR signaling.

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“…For instance, Crk interacts with phosphatidylinositol kinase, activating Akt [49], which also influences cancer cell adhesion in response to pressure [7]. Our results indicate that paxillin phosphorylation in human colon cancer cells in response to pressure facilitates paxillin-Crk binding, which is also required for the stimulation of adhesion.…”

Section: Discussionmentioning

confidence: 74%

Pressure activates colon cancer cell adhesion via paxillin phosphorylation, Crk, Cas, and Rac1

Downey

Craig

Basson

2008

Cell. Mol. Life Sci.

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Physical forces can activate colon cancer cell adhesion, critical for metastasis. Paxillin is phosphorylated by FAK and required for pressure-stimulated adhesion. However, whether paxillin acts as an inert scaffolding protein or whether paxillin phosphorylation is required is unknown. Transfection with paxillin point-phosphorylation mutants demonstrated that phosphorylation at tyrosines 31 and 118 together is necessary for pressure-stimulated adhesion. We further evaluated potential paxillin partners. Reducing the adaptor protein Crk or the focal adhesion protein p130 Cas blocked pressure-stimulated adhesion. Furthermore, Crk and p130 Cas both displayed increased coimmunoprecipitation with paxillin in response to increased pressure, except in cells transfected with a Y31Y118 paxillin mutant. Inhibiting the small GTPase Rac1 also abolished pressurestimulated adhesion, and reducing paxillin by siRNA blocked Rac1 phosphorylation by pressure. Thus, paxillin phosphorylation at tyrosines 31 and 118 together is necessary for pressure-induced adhesion. Paxillin, Crk and Cas form a trimeric complex that activates Rac1 and mediates this effect.

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Physiological signals and oncogenesis mediated through Crk family adapter proteins

Cited by 129 publications

References 154 publications

JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway

JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway

T cell development and function in CrkL‐deficient mice

Pressure activates colon cancer cell adhesion via paxillin phosphorylation, Crk, Cas, and Rac1

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