Abstract
BackgroundThe non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. Abl also is a critical regulator of normal development, playing conserved roles in regulating cell behavior, brain development and morphogenesis. Drosophila offers a superb model for studying Abl’s normal function, because, unlike mammals, there is only a single fly Abl family member. In exploring the mechanism of action of multi-domain scaffolding proteins like Abl, one route is to define the roles of their individual domains. Research into Abl’s diverse roles in embryonic morphogenesis revealed many surprises. For instance, kinase activity, while important, is not crucial for all Abl activities, and the C-terminal F-actin binding domain plays a very modest role. This turned our attention to one of Abl’s least understood features—the long intrinsically-disordered region (IDR) linking Abl’s kinase and F-actin binding domains. The past decade revealed unexpected, important roles for IDRs in diverse cell functions, as sites of posttranslational modifications, mediating multivalent interactions and enabling assembly of biomolecular condensates via phase separation. Previous work deleting conserved regions in Abl’s IDR revealed an important role for a PXXP motif, but did not identify any other essential regions.MethodsHere we extend this analysis by deleting the entire IDR, and asking whether Abl∆IDR rescues the diverse roles of Abl in viability and embryonic morphogenesis in Drosophila.ResultsThis revealed that the IDR is essential for embryonic and adult viability, and for cell shape changes and cytoskeletal regulation during embryonic morphogenesis, and, most surprisingly, revealed a role in modulating protein stability.ConclusionOur data provide new insights into the role of the IDR in an important signaling protein, the non-receptor kinase Abl, suggesting that it is essential for all aspects of protein function during embryogenesis, and revealing a role in protein stability. These data will stimulate new explorations of the mechanisms by which the IDR regulates Abl stability and function, both in Drosophila and also in mammals. They also will stimulate further interest in the broader roles IDRs play in diverse signaling proteins.73VeGkEcreJz_7Qb6G2WNGVideo
Highlights
The non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy
Rogers et al Cell Commun Signal (2021) 19:27 (See figure on page.) Fig. 1 Generating Abl∆intrinsically-disordered region (IDR) and testing its ability to rescue adult and embryonic viability. a Diagram of human Abl and Ablrelated gene (Arg) and Drosophila Abl, showing conserved domains/motifs as well as motifs in the IDR that vary between family members. b All Abl family members share a region between the structured kinase and F-actin binding domains that is predicted to be disordered
The Drosophila abl gene encodes several splice variants that differ in the inclusion or exclusion of two exons: an 18 aa axon in the unstructured N-terminal region prior to the Src homology 3 (SH3) domain, and a 115 aa sequence in the C-terminal region of the IDR
Summary
The non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. D Assessment of the ability of Abl∆IDR to rescue the viability of abl4/DfAbl adults, normalized to rescue by our wildtype Abl transgene, and compared to rescue by some of our previously tested mutants. E Assessment of the ability of Abl∆IDR to rescue embryonic viability of the progeny of abl4/DfAbl females mated to abl4/+ males, compared to rescue by some of our previously tested mutants. Line indicates degree of rescue by our wildtype Abl transgene chromosomes 9 and 22 present only in leukocytes from patients with chronic myelogenous leukemia It provided the first molecular link between genetics and cancer, and led to the realization that Abelson kinase (Abl) is the initiating oncogene in many cases of chronic myelogenous and acute lymphoblastic leukemia [1]. Drugs targeting Abl kinase activity like Gleevec (Imatinib) have emerged as paradigms of targeted therapy [2, 3], and spurred the development of similar inhibitors of other oncogenic kinases
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