J Biol Chem. 2005 Nov 11;280(45):37974-87. Epub 2005 Sep 6.

Epidermal growth factor induces tyrosine phosphorylation, membrane insertion, and activation of transient receptor potential channel 4.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Odell, A. F., Scott, J. L., Van Helden, D. F.,
["School of Biomedical Sciences, Level 5 MSB, University of Newcastle, Callaghan, New South Wales, Australia. adam.odell@newcastle.edu.au"]
Various members of the canonical family of transient receptor potential channels (TRPCs) exhibit increased cation influx following receptor stimulation or Ca(2+) store depletion. Tyrosine phosphorylation of TRP family members also results in increased channel activity; however, the link between the two events is unclear. We report that two tyrosine residues in the C terminus of human TRPC4 (hTRPC4), Tyr-959 and Tyr-972, are phosphorylated following epidermal growth factor (EGF) receptor stimulation of COS-7 cells. This phosphorylation was mediated by Src family tyrosine kinases (STKs), with Fyn appearing to be the dominant kinase. In addition, EGF receptor stimulation induced the exocytotic insertion of hTRPC4 into the plasma membrane dependent on the activity of STKs and was accompanied by a phosphorylation-dependent increase in the association of hTRPC4 with Na(+)/H(+) exchanger regulatory factor. Furthermore, this translocation and association was defective upon mutation of Tyr-959 and Tyr-972 to phenylalanine. Significantly, inhibition of STKs was concomitant with a reduction in Ca(2+) influx in both native COS-7 cells and hTRPC4-expressing HEK293 cells, with cells expressing the Y959F/Y972F mutant exhibiting a reduced EGF response. These findings represent the first demonstration of a mechanism for phosphorylation to modulate TRPC channel function.
PMID: 16144838External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Screening Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Experimental screening Non-experimental screening Reference
TRP channel construct Interactor source
TRP channel Interactor Method Species Region Species Organ/tissue Sample type
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 FYN Inference Prediction 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 LYN Inference Prediction 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 SRC Inference Prediction 16144838
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Screening Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vitro validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Validation: In vivo validation Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Characterization Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b Functional consequence Arrow2 1fb2b8a5ad55723bad55961567d092af30310a7cf44ded6f695fc2aa4753ec2b top
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 FYN Co-immunoprecipitation COS-7 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 FYN Co-immunoprecipitation COS-7 Human Full-length Not specifed Full-length 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 LYN Co-immunoprecipitation COS-7 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 LYN Co-immunoprecipitation COS-7 Human Full-length Not specifed Full-length 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 NHERF1 Co-immunofluorescence staining COS-7 Human Full-length Not specifed Full-length 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 NHERF1 Co-immunoprecipitation COS-7 Human Full-length Not specifed Full-length 16144838
TRPC4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 SRC Co-immunoprecipitation COS-7 Human Full-length Not specifed Full-length 16144838
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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