The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation

J Cell Mol Med. 2020 Dec;24(24):14633-14638. doi: 10.1111/jcmm.16014. Epub 2020 Oct 28.

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is mainly caused by variants in the PKHD1 gene, encoding fibrocystin (FC), a large transmembrane protein of incompletely understood cellular function. Here, we show that a C-terminal fragment of human FC can suppress a signalling module of the kinase SRC and signal transducer and activator of transcription 3 (STAT3). Consistently, we identified truncating genetic variants specifically affecting the cytoplasmic tail in ARPKD patients, found SRC and the cytoplasmic tail of fibrocystin in a joint dynamic protein complex and observed increased activation of both SRC and STAT3 in cyst-lining renal epithelial cells of ARPKD patients.

Keywords: cilia; genetic kidney diseases; polycystic kidney disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Immunohistochemistry
  • Phosphorylation
  • Polycystic Kidney, Autosomal Recessive / etiology
  • Polycystic Kidney, Autosomal Recessive / metabolism*
  • Polycystic Kidney, Autosomal Recessive / pathology
  • Protein Interaction Domains and Motifs*
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*
  • src-Family Kinases / metabolism*

Substances

  • PKHD1 protein, human
  • Receptors, Cell Surface
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • src-Family Kinases