@article{d196bc6b2fb14bf1ae14a212a4f83fd2,
title = "An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation",
abstract = "The ErbB4 receptor isoforms JM-a and JM-b differ within their extracellular juxtamembrane (eJM) domains. Here, ErbB4 isoforms are used as a model to address the effect of structural variation in the eJM domain of receptor tyrosine kinases (RTK) on downstream signaling. A specific JM-a-like sequence motif is discovered, and its presence or absence (in JM-b-like RTKs) in the eJM domains of several RTKs is demonstrated to dictate selective STAT activation. STAT5a activation by RTKs including the JM-a like motif is shown to involve interaction with oligosaccharides of N-glycosylated cell surface proteins such as β1 integrin, whereas STAT5b activation by JM-b is dependent on TYK2. ErbB4 JM-a- and JM-b-like RTKs are shown to associate with specific signaling complexes at different cell surface compartments using analyses of RTK interactomes and super-resolution imaging. These findings provide evidence for a conserved mechanism linking a ubiquitous extracellular motif in RTKs with selective intracellular STAT signaling.",
author = "Katri Vaparanta and Anne Jokilammi and Mahlet Tamirat and Merilahti, {Johannes A.M.} and Kari Salokas and Markku Varjosalo and Johanna Ivaska and Johnson, {Mark S.} and Klaus Elenius",
note = "Funding Information: We thank Minna Santanen, Mika Savisalo, and Maria Tuominen for excellent technical assistance, Jukka Lehtonen (Biocenter Finland bioinformatics network) for scientific IT support and CSC IT Center for Science for supercomputing. STAT5b tyrosine to phenylalanine point mutant plasmid constructs were a kind gift from the laboratory of Jeffrey M. Rosen. We thank Sauli Haataja for loaning lectin reagents. Turku Doctoral Program of Molecular Medicine, {\AA}bo Akademi Graduate School and Doctoral Network of Informational and Structural Biology are acknowledged for doctoral training. 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, The Emil Aaltonen Foundation, The Maud Kuistila Memorial Foundation, Orion Research Foundation, K. Albin Johanssons stiftelse, the Foundation of {\AA}bo Akademi and the Joe, Pentti and Tor Borg Memorial Fund. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-34539-4",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}