pTyr signalling is often dysregulated in cancers and other diseases. Examples of such adaptors include Shc1, Crk, Nck, and Grb2 that also contain other interaction modules such as SH3 domains that bind polyproline (PxxP) motifs ( Bywaters and Rivera, 2021 Mayer, 2015). SH2 domains are present in kinases, phosphatases as well as adaptor proteins that lack enzymatic activity but couple upstream signalling events to downstream function ( Liu and Nash, 2012). Pathways including EGF and insulin receptor signalling, as well as T cell activation rely on pTyr motifs interacting with SH2 domains ( Blumenthal and Burkhardt, 2020 Lemmon and Schlessinger, 2010). Multicellular animals extensively use phosphotyrosine (pTyr) signals for growth, communication, movement, and differentiation ( Jin and Pawson, 2012 Lim and Pawson, 2010). It also has important implications for regulation of physiological networks, including those undergoing phase transitions. This finding may explain why the relative positions of pTyr motifs are frequently conserved in proteins from widely different species. This suggests that the relative position of pTyr adaptor binding sites is optimised for signal output. Manipulating the position of pTyr motifs in A36 and the unrelated p14 from Orthoreovirus, we find that only specific spatial arrangements of Nck and Grb2 binding sites result in robust N-WASP recruitment, Arp2/3 complex driven actin polymerisation and viral spread. This network involves two pTyr motifs in the viral protein A36 that recruit the adaptors Nck and Grb2 upstream of N-WASP and Arp2/3 complex-mediated actin polymerisation. We have now investigated this parameter in the operation of the signalling cascade driving actin-based motility and spread of Vaccinia virus.
The concept of phase separation has recently changed our appreciation of multivalent networks, however, the role of pTyr motif positioning in their function remains to be explored. Phosphotyrosine (pTyr) motifs in unstructured polypeptides orchestrate important cellular processes by engaging SH2-containing adaptors to assemble complex signalling networks.
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