Mol Cell Biol. 2005 Sep;25(18):8285-98.
PKD2 functions as an epidermal growth factor-activated plasma membrane channel.
Ma, R., Li, W. P., Rundle, D., Kong, J., Akbarali, H. I., Tsiokas, L.,
["Department of Cell Biology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA."]
["Department of Cell Biology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA."]
PKD2, or polycystin 2, the product of the gene mutated in type 2 autosomal dominant polycystic kidney disease, belongs to the transient receptor potential channel superfamily and has been shown to function as a nonselective cation channel in the plasma membrane. However, the mechanism of PKD2 activation remains elusive. We show that PKD2 overexpression increases epidermal growth factor (EGF)-induced inward currents in LLC-PK(1) kidney epithelial cells, while the knockdown of endogenous PKD2 by RNA interference or the expression of a pathogenic missense variant, PKD2-D511V, blunts the EGF-induced response. Pharmacological experiments indicate that the EGF-induced activation of PKD2 occurs independently of store depletion but requires the activity of phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K). Pipette infusion of purified phosphatidylinositol-4,5-bisphosphate (PIP(2)) suppresses the PKD2-mediated effect on EGF-induced conductance, while pipette infusion of phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) does not have any effect on this conductance. Overexpression of type Ialpha phosphatidylinositol-4-phosphate 5-kinase [PIP(5)Kalpha], which catalyzes the formation of PIP(2), suppresses EGF-induced currents. Biochemical experiments show that PKD2 physically interacts with PLC-gamma2 and EGF receptor (EGFR) in transfected HEK293T cells and colocalizes with EGFR and PIP(2) in the primary cilium of LLC-PK(1) cells. We propose that plasma membrane PKD2 is under negative regulation by PIP(2). EGF may reduce the threshold of PKD2 activation by mechanical and other stimuli by releasing it from PIP(2)-mediated inhibition.
PMID: 16135816

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Screening
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Experimental screening | Non-experimental screening | Reference | ||||||||
TRP channel construct | Interactor source | |||||||||
TRP channel | Interactor | Method | Species | Region | Species | Organ/tissue | Sample type | |||
TRPP1 |
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EGFR | Inference | Prediction | 16135816 | |||||
TRPP1 |
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PLCƣ2 | Inference | Prediction | 16135816 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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Validation: In vivo validation
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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 | ||||
TRPP1 |
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EGFR | Co-immunoprecipitation | HEK293T | Human | Full-length | Human | Full-length | 16135816 | |
TRPP1 |
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EGFR | Co-immunofluorescence staining | LLC-PK1 | 16135816 | |||||
TRPP1 |
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PLCƣ2 | Co-immunoprecipitation | HEK293T | Human | Full-length | Not specified | Full-length | 16135816 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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Characterization
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Binding region mapping | Stoichiometry | Affinity (Kd) | Reference | |||||||
TRP channel | Interactor | |||||||||
TRP channel | Interactor | Method | Species | Region | Species | Region | ||||
TRPP1 |
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EGFR | Co-immunoprecipitation | Human | 1-871 | Human | Not determined | 16135816 | ||
TRPP1 |
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PLCƣ2 | Co-immunoprecipitation | Human | 1-379 | Not specified | Not determined | 16135816 |
(
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
