An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation

: Vaparanta Katri, Jokilammi Anne, Tamirat Mahlet, Merilahti Johannes AM, Salokas Kari, Varjosalo Markku, Ivaska Johanna, Johnson Mark S, Elenius Klaus

: 2022

: Nature Communications

: Nature communications

: Nat Commun

: 13

: 1

: 2041-1723

DOI: https://doi.org/10.1038/s41467-022-34539-4

: https://research.utu.fi/converis/portal/detail/Publication/177428746

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.

s41467-022-34539-4.pdf