Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation.

Zhao, Yuhang; Sudol, Marius; Hanafusa, Hidesaburô; Krueger, James G.

doi:10.1073/pnas.89.17.8298

Cited by 96 publications

(88 citation statements)

References 36 publications

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“…The mechanisms by which changes in extracellular Ca 2ϩ signal a change in the proliferation of keratinocytes have not yet been established. Exposing keratinocytes to elevated extracellular Ca 2ϩ is associated with an increase in the kinase activity of c-SRC and a decrease in the activity of c-YES (6,32); the mechanism producing this response has not been established. An increase in the apparent phosphorylation of an approximately 62-kDa protein co-immunoprecipitated with antirasGAP antibodies has also been demonstrated and attributed to activation of a calcium-binding receptor as opposed to Ca 2ϩ influx (7,9).…”

Section: Discussionmentioning

confidence: 99%

“…Elevation of extracellular calcium levels has been associated with increased c-SRC kinase activity in keratinocytes (6). If the CaR is responsible for modulating c-SRC activity in response to changes in extracellular calcium, then an increase in SRC kinase activity should be observed in the presence of Gd 3ϩ , which binds and activates the CaR without passing through calcium channels.…”

Section: Effect Of Car Activity On C-src Kinase Activitymentioning

confidence: 99%

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Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

McNeil¹,

Hobson

Nipper

et al. 1998

Journal of Biological Chemistry

212

124

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Changes in the concentration of extracellular calcium can affect the balance between proliferation and differentiation in several cell types, including keratinocytes, breast epithelial cells, and fibroblasts. This report demonstrates that elevation of extracellular calcium stimulates proliferation-associated signaling pathways in rat fibroblasts and implicates calcium-sensing receptors (CaR) as mediators of this response. Rat-1 fibroblasts express CaR mRNA and protein and respond to known agonists of the CaR with increased IP 3 production and release of intracellular calcium. Agonists of the CaR can stimulate increased c-SRC kinase activity and increased extracellular signal-regulated kinase 1/mitogen-activated protein kinase activity. Both of the increases in SRC activity and mitogen-activated protein kinase activation are blocked in the presence of a nonfunctional mutant of the CaR, R796W. Proliferation of wild-type Rat-1 cells is sensitive to changes in extracellular calcium, but expression of the nonfunctional CaR mutant or inhibition of the calcium-dependent increase in SRC kinase activity block the proliferative response to calcium. These results provide evidence of a novel signal transduction pathway modulating the response of fibroblasts to extracellular calcium and imply that calciumsensing receptors may play a role in regulating cell growth in response to extracellular calcium, in addition to their well known function in systemic calcium homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Car Activity On C-src Kinase Activitymentioning

confidence: 99%

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

McNeil¹,

Hobson

Nipper

et al. 1998

Journal of Biological Chemistry

212

124

View full text Add to dashboard Cite

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“…Activation of Src kinase requires Ca 2+ and can occur as a result of increased [Ca 2+ ] i (22,23). In our previous study, we have shown lysoPC-induced TRPC6 externalization in BAECs was not blocked in Ca 2+ -free KR buffer or by using BAPTA/AM (25 μM) (3).…”

Section: Discussionmentioning

confidence: 99%

Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation

Chaudhuri

Rosenbaum

Sinharoy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels leading to inhibition of endothelial cell (EC) migration in vitro and delayed EC healing of arterial injuries in vivo. The precise mechanism through which lysoPC activates TRPC6 channels is not known, but calmodulin (CaM) contributes to the regulation of TRPC channels. Using site-directed mutagenesis, cDNAs were generated in which Tyr 99 or Tyr 138 of CaM was replaced with Phe, generating mutant CaM, Phe 99 -CaM, or Phe 138 -CaM, respectively. In ECs transiently transfected with pcDNA3.1-myc-His-Phe 99 -CaM, but not in ECs transfected with pcDNA3.1-myc-His-Phe 138 -CaM, the lysoPC-induced TRPC6-CaM dissociation and TRPC6 externalization was disrupted. Also, the lysoPC-induced increase in intracellular calcium concentration was inhibited in ECs transiently transfected with pcDNA3.1-myc-His-Phe 99 -CaM. Blocking phosphorylation of CaM at Tyr 99 also reduced CaM association with the p85 subunit and subsequent activation of phosphatidylinositol 3-kinase (PI3K). This prevented the increase in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the translocation of TRPC6 to the cell membrane and reduced the inhibition of EC migration by lysoPC. These findings suggest that lysoPC induces CaM phosphorylation at Tyr 99 by a Src family kinase and that phosphorylated CaM activates PI3K to produce PIP3, which promotes TRPC6 translocation to the cell membrane.endothelial | calmodulin | PI3 kinase | TRPC6

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“…In addition, both proteins colocalize in discrete structures in specific areas in the periphery of the cell, indicating that these focal adhesions may differ in terms of their protein content and partners that are mediated by the PDZ domains of MDA-9/syntenin. Of potential interest, both proteins also colocalize in or near the cell nucleus, suggesting that these two proteins could interact and may promote transcriptional activities (7,8,19).…”

Section: Mda-9/syntenin Physically Interacts With C-src Which Correlmentioning

confidence: 99%

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

Boukerche

Prévot

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

118

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The scaffold PDZ-domain containing protein mda-9/syntenin functions as a positive regulator of cancer cell progression in human melanoma and other tumors. mda-9/Syntenin regulates cell motility and invasion by altering defined biochemical and signaling pathways, including focal adhesion kinase (FAK), p38 mitogenactivated protein kinase (MAPK) and NF-B, but precisely how mda-9/syntenin organizes these multiprotein signaling complexes is not well understood. Using a clinically relevant human melanoma model, we demonstrate that mda-9/syntenin physically interacts with c-Src and this communication correlates with an increase in FAK/c-Src complex formation and c-Src activation. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin or addition of c-Src siRNA, suppresses melanoma cell migration, anchorage-independent growth, and spontaneous tumor cell dissemination in vivo in a human melanoma animal metastasis model. These data are compatible with a model wherein interaction of MDA-9/syntenin with c-Src promotes the formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread. These provocative findings highlight mda-9/ syntenin and its interacting partners as promising therapeutic targets for intervention of metastasis. Understanding and preventing this process and its dire consequences remain formidable obstacles in achieving successful treatment outcomes in advanced cancer patients. In the context of advanced melanoma, the response rate of patients with metastatic disease to single agent chemotherapy or combination therapies is frequently less than 10% (1). Given this bleak picture, it is vital to develop new, efficacious, and rationally designed treatment strategies to, ideally, prevent or effectively treat metastasis. In this context, defining relevant genes that are seminal regulators of metastasis provide an entry point for developing improved therapies.Melanoma differentiation associated gene-9 (mda-9) was cloned in our laboratory (2, 3) as a unique gene displaying biphasic expression during terminal differentiation of human melanoma cells treated with a combination of fibroblast IFN (IFN-␤) and the antileukemic compound mezerein (MEZ). These changes are consistent with early enhancement followed by decreased expression during the course of reversion of the cancer phenotype in melanoma cells (2, 3). mda-9, also called syntenin, expression displays an inverse relationship with tumor progression, with lowlevel expression in melanocytes and radial growth phase (RGP) primary melanoma versus elevated expression in vertical growth phase (VGP) primary melanoma and metastatic melanomas (4, 5). The level of mda-9/syntenin is also elevated in multiple additional cancers, including breast and gastric carcinomas, suggesting an expanded involvement in tumor progression (6). Recently, we confirmed the importance of mda-9/syntenin in metastasis in vivo, providing direct support for mda-9/syntenin as an essential gene controlling melanoma progres...

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Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation.

Cited by 96 publications

References 36 publications

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

Functional Calcium-sensing Receptors in Rat Fibroblasts Are Required for Activation of SRC Kinase and Mitogen-activated Protein Kinase in Response to Extracellular Calcium

Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation

mda -9/Syntenin promotes metastasis in human melanoma cells by activating c-Src

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