Universität zu Köln

Talbot, Jeffrey J., Song, Xuewen, Wang, Xiaofang, Rinschen, Markus M., Doerr, Nicholas, LaRiviere, Wells B., Schermer, Bernhard ORCID: 0000-0002-5194-9000, Pei, York P., Torres, Vicente E. and Weimbs, Thomas (2014). The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation. J. Am. Soc. Nephrol., 25 (8). S. 1737 - 1749. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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Abstract

Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Src-dependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src./STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to CAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR- or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Talbot, Jeffrey J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Song, Xuewen UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Xiaofang UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Doerr, Nicholas UNSPECIFIED UNSPECIFIED UNSPECIFIED LaRiviere, Wells B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED Pei, York P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Torres, Vicente E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weimbs, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-432915
DOI:	10.1681/ASN.2013091026
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	25
Number:	8
Page Range:	S. 1737 - 1749
Date:	2014
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITION; KIDNEY-DISEASE ADPKD; SIGNALING PATHWAYS; CYST FORMATION; TRANSCRIPTION FACTORS; PKA PHOSPHORYLATION; CELL-PROLIFERATION; EPITHELIAL-CELLS; RENAL INJURY Multiple languages Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43291