Premium
An extracellular motif localizes receptor tyrosine kinases to membrane platforms for selective STAT activation
Author(s) -
Vaparanta Katri Mataleena,
Jokilammi Anne,
Tamirat Mahlet,
Hemanthakumar Karthik Amudhala,
Merilahti Johannes,
Kivelä Riikka,
Alitalo Kari,
Johnson Mark S,
Elenius Klaus
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.476.30
Subject(s) - gene isoform , receptor tyrosine kinase , erbb4 , phosphorylation , signal transduction , kinase , receptor , protein kinase domain , extracellular , biology , microbiology and biotechnology , mutant , biochemistry , gene
The ErbB4 receptor isoforms JM‐a and JM‐b differ within their extracellular juxtamembrane (eJM) domains. We utilized ErbB4 isoforms as a model to address whether structural variation in the extracellular juxtamembrane (eJM) domain of receptor tyrosine kinases (RTK) affects downstream signaling. The JM‐a isoform was found to selectively signal through STAT5a, and JM‐b through STAT5b and STAT3. The activation mechanisms of STAT5a and STAT5b involved different signaling complexes, and were independent of proteolytic cleavage unique for ErbB4 JM‐a. The two JM isoforms demonstrated localization to different plasma membrane subcompartments. Mutational analysis identified the JM‐a residue H631 as critical for STAT5 subtype activation and plasma membrane localization. JM‐a‐ and JM‐b‐specific sequence motifs were discovered also in several other RTKs including EGFR, ErbB2, ErbB3, EPHA2, FGFR3, IRR, TIE1, and TYRO3, and the presence of these motifs similarly determined selective STAT activation and plasma membrane localization. Finally, analysis of cardiomyocytes supported a biological role for ErbB4 JM‐b/STAT5b signaling in regulating cardiomyocyte hypertrophy. These findings indicate a novel function for eJM domain in RTK signaling. Support or Funding Information This work was financially supported by the Academy of Finland, the Cancer Foundation of Finland, the Sigrid Juselius Foundation, the Turku University Central Hospital, the Cancer Society of Southwestern Finland, Turku University Foundation, the Finnish Cultural Foundation, Varsinais‐Suomi Regional Fund, the Finnish Foundation for Cardiovascular Research, Foundation of Åbo Akademi and the Joe, Pentti and Tor Borg Memorial Fund.A model in which a similarity motif in the eJM domain of an RTK results in significant changes in the biological responses by selectively activating two different STAT5 pathways. Two subclasses of RTKs, represented by the ErbB4 isoforms JM‐a and JM‐b, are located in separate plasma membrane microdomains. This differential location leads to selective activation of STAT5a and STAT5b, respectively, through different signaling mechanisms, leading to differential transcriptional responses.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .