The Src Family Kinases, Fgr, Fyn, Lck, and Lyn, Colocalize With Coated Membranes in Platelets

Stenberg, Paula E.; Pestina, Tamara I.; Barrie, Rosemary; Jackson, Carl W.

doi:10.1182/blood.v89.7.2384

Cited by 58 publications

(24 citation statements)

References 27 publications

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“…Fyn was seen in small intracellular foci within 5 min of addition of CSF-1 (Fig. 4), indicating that it may undergo endocytosis during CSF-1 signaling, which is consistent with the observation that Fyn localizes to early endosomes in Fyn-expressing cell lines and to vesicles in human lymphocytes and platelets [41,52,53]. Thus, Fyn may regulate or be regulated by endocytosis in macrophages and other cell types.…”

Section: Discussionsupporting

confidence: 87%

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration

Dwyer

Mouchemore

Steer

et al. 2016

Journal of Leukocyte Biology

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A major role of colony-stimulating factor-1 is to stimulate the differentiation of mononuclear phagocytic lineage cells into adherent, motile, mature macrophages. The colony-stimulating factor-1 receptor transduces colony-stimulating factor-1 signaling, and we have shown previously that phosphatidylinositol 3-kinase p110δ is a critical mediator of colony-stimulating factor-1-stimulated motility through the colony-stimulating factor-1 receptor pY721 motif. Src family kinases are also implicated in the regulation of macrophage motility and in colony-stimulating factor-1 receptor signaling, although functional redundancy of the multiple SFKs expressed in macrophages makes it challenging to delineate their specific functions. We report a comprehensive analysis of individual Src family kinase expression in macrophage cell lines and primary macrophages and demonstrate colony-stimulating factor-1-induced changes in Src family kinase subcellular localization, which provides clues to their distinct and redundant functions in macrophages. Moreover, expression of individual Src family kinases is both species specific and dependent on colony-stimulating factor-1-induced macrophage differentiation. Hck associated with the activated colony-stimulating factor-1 receptor, whereas Lyn associated with the receptor in a constitutive manner. Consistent with this, inhibitor studies revealed that Src family kinases were important for both colony-stimulating factor-1 receptor activation and colony-stimulating factor-1-induced macrophage spreading, motility, and invasion. Distinct colony-stimulating factor-1-induced changes in the subcellular localization of individual SFKs suggest specific roles for these Src family kinases in the macrophage response to colony-stimulating factor-1.

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Section: Discussionsupporting

confidence: 87%

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration

Dwyer

Mouchemore

Steer

et al. 2016

Journal of Leukocyte Biology

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“…All the SFKs can be associated with lipid rafts, but the distribution of each SFK in the membrane differs depending upon the N-terminal modifications (Brown and Cooper, 1996;Stenberg et al, 1997). Most SFKs, such as Fyn and Lck, have both myristate and palmitate moieties (Resh, 1994), allowing their preferential localization in lipid rafts.…”

Section: Discussionmentioning

confidence: 99%

The Lipid Raft-Anchored Adaptor Protein Cbp Controls the Oncogenic Potential of c-Src

et al. 2008

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The tyrosine kinase c-Src is upregulated in various human cancers irrespective of its negative regulator Csk, but the regulatory mechanisms remain unclear. Here, we show that a lipid raft-anchored Csk adaptor, Cbp/PAG, is directly involved in controlling the oncogenicity of c-Src. Using Csk-deficient cells that can be transformed by c-Src overexpression, we found that Cbp expression is markedly downregulated by c-Src activation and re-expression of Cbp efficiently suppresses c-Src transformation as well as tumorigenesis. Cbp-deficient cells are more susceptible to v-Src transformation than their parental cells. Upon phosphorylation, Cbp specifically binds to activated c-Src and sequesters it in lipid rafts, resulting in an efficient suppression of c-Src function independent of Csk. In some human cancer cells and tumors, Cbp is downregulated and the introduction of Cbp significantly suppresses tumorigenesis. These findings indicate a potential role for Cbp as a suppressor of c-Src-mediated tumor progression.

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“…SFKs (Src family kinases) have been shown to play important roles in platelet activation, aggregation and adhesion [8][9][10][11]. Platelets express six SFKs, including p60 Src [12][13][14][15], p59 Fyn [14][15][16][17], p56 Lck [15,17], p62 Yes [15,18], p55 Fgr [15] and p53/56 Lyn [16,17]. Among these, p59 Fyn and p53/56 Lyn are involved in signal transduction by the GPVI-FcR γ -chain collagen receptor complex [8], whereas p60 Src plays an important role in α IIb β 3 -mediated signal transduction [11].…”

Section: Introductionmentioning

confidence: 99%

Paxillin family members function as Csk-binding proteins that regulate Lyn activity in human and murine platelets

Rathore

Okada

Newman

et al. 2007

Biochemical Journal

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SFKs (Src family kinases) contribute importantly to platelet function in haemostasis. SFK activity is controlled by Csk (C-terminal Src kinase), which phosphorylates a C-terminal tyrosine residue on SFKs, resulting in inhibition of SFK activity. Csk is recruited to sites of SFK activity by tyrosine-phosphorylated Csk-binding proteins. Paxillin, a multidomain adaptor protein, has been shown to act as a Csk-binding protein and to inhibit Src activity during growth factor signalling. Human platelets express Hic-5, a member of the paxillin family; however, its ability to act as a Csk-binding protein has not been characterized. We sought to identify and characterize the ability of paxillin family members to act as Csk-binding proteins during platelet activation. We found that murine and human platelets differ in the complement of paxillin family members expressed. Human platelets express Hic-5, whereas murine platelets express paxillin and leupaxin in addition to Hic-5. In aggregating human platelets, Hic-5 was tyrosine phosphorylated and recruited Csk via its SH2 domains. In aggregating murine platelets, however, Csk bound preferentially to paxillin, even though both paxillin and Hic-5 were abundantly present and became tyrosine phosphorylated. The SFK Lyn, but not Src or Fyn, was associated with paxillin family members in resting and aggregated human and murine platelets. Lyn, however, was phosphorylated on its C-terminal inhibitory tyrosine residue only following platelet aggregation, which was coincident with recruitment of Csk to paxillin and/or Hic-5 in a manner dependent on prior alpha(IIb)beta3 engagement. These observations support the notion that Hic-5 and paxillin function as negative feedback regulators of SFKs in aggregated platelets and that, when both are present, paxillin is preferentially used.

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The Src Family Kinases, Fgr, Fyn, Lck, and Lyn, Colocalize With Coated Membranes in Platelets

Cited by 58 publications

References 27 publications

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration

The Lipid Raft-Anchored Adaptor Protein Cbp Controls the Oncogenic Potential of c-Src

Paxillin family members function as Csk-binding proteins that regulate Lyn activity in human and murine platelets

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