An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation

Katri Vaparanta, Anne Jokilammi, Mahlet Tamirat, Johannes A.M. Merilahti, Kari Salokas, Markku Varjosalo, Johanna Ivaska, Mark S. Johnson, Klaus Elenius*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)
39 Downloads (Pure)

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.

Original languageEnglish
Article number6953
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022
MoE publication typeA1 Journal article-refereed

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