The Lnk/SH2B adaptor provides a fail-safe mechanism to establish the Insulin receptor-Chico interaction

Almudí, Isabel; Poernbacher, Ingrid; Hafen, Ernst; Stocker, Hugo

doi:10.1186/1478-811x-11-26

Cited by 26 publications

(17 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…X11L has been implicated in amyloid precursor protein (APP) regulation in both Drosophila and mammalian cells (Hase et al 2002;Gross et al 2008), with no reported connections to either Jak/Stat or tyrosine kinase signaling. Lnk negatively feeds back on Jak/Stat signaling in mammalian cells, although in Drosophila it has been studied as a positive regulator of insulin/insulin-like growth factor signaling (Werz et al 2009;Oh et al 2010;Slack et al 2010;Almudi et al 2013). The Jak/Stat ligands unpaired (Upd) 2 and 3 influence insulin signaling in Drosophila (Rajan and Perrimon 2012; Woodcock et al 2015), thus potentially implicating Lnk in Jak/Stat signaling in flies.…”

Section: Resultsmentioning

confidence: 99%

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

2016

View full text Add to dashboard Cite

The transcriptional coactivator and phosphatase eyes absent (Eya) is dynamically compartmentalized between the nucleus and cytoplasm. Although the nuclear transcriptional circuits within which Eya operates have been extensively characterized, understanding of its cytoplasmic functions and interactions remains limited. Our previous work showed that phosphorylation of Drosophila Eya by the Abelson tyrosine kinase can recruit Eya to the cytoplasm and that eya-abelson interactions are required for photoreceptor axons to project to correct layers in the brain. Based on these observations, we postulated that photoreceptor axon targeting might provide a suitable context for identifying the cytoplasmic signaling cascades with which Eya interacts. Using a dosesensitive eya misexpression background, we performed an RNA interference-based genetic screen to identify suppressors. Included among the top 10 hits were nonreceptor tyrosine kinases and multiple members of the Jak/Stat signaling network (hop, Stat92E, Socs36E, and Socs44A), a pathway not previously implicated in axon targeting. Individual loss-of-function phenotypes combined with analysis of axonal projections in Stat92E null clones confirmed the importance of photoreceptor autonomous Jak/Stat signaling. Experiments in cultured cells detected cytoplasmic complexes between Eya and Hop, Socs36E and Socs44A; the latter interaction required both the Src homology 2 motif in Socs44A and tyrosine phosphorylated Eya, suggesting direct binding and validating the premise of the screen. Taken together, our data provide new insight into the cytoplasmic phosphotyrosine signaling networks that operate during photoreceptor axon guidance and suggest specific points of interaction with Eya.KEYWORDS SH2; genetic screen; retinal determination network; eye development; Socs44A A remarkable feature of multicellular animal development is that the complexity and diversity in tissue type and patterning is achieved using fewer than a dozen signaling pathways, including Notch, receptor tyrosine kinase, Wnt, Hedgehog, TGFb, Jak/Stat, and Hippo. These cascades are repeatedly deployed in different contexts to regulate the majority of the critical proliferation, survival, specification, and differentiation decisions (reviewed in Voas and Rebay 2004;Housden and Perrimon 2014). One strategy to achieve context-specific developmental regulation is for proteins and pathways to function together in interconnected networks. Further, individual proteins within these networks may encode multiple independent functions that can be executed in distinct parts of the cell, cell types, or stages of development. In this way, even a modest number of individual proteins and core pathways can create vast combinatorial possibilities.Eyes absent (Eya), a protein conserved from plants to humans, presents an ideal model to study integration because its multifunctionality and dynamic subcellular localization provide opportunities for interaction with many signaling pathways (reviewed in Jemc andRebay 2007 an...

show abstract

Section: Resultsmentioning

confidence: 99%

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

2016

View full text Add to dashboard Cite

show abstract

“…Almudi et al [128] showed that Drosophila SH2B binds to both Chico and insulin receptors in Drosophila cells. SH2B-deficient flies display defects in insulin/IGF signaling, developmental delay, small size, and female sterility [4,5] .…”

Section: Metabolic Function Of Sh2b1 Is Evolutionarily Conservedmentioning

confidence: 99%

SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

View full text Add to dashboard Cite

The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo-or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/ IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuronspecific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. Key words: Obesity; Type 2 diabetes; Leptin resistance; Insulin resistance; Glucose intolerance; Hypothalamus; Energy balance; Food intake; Hyperphagia; Nonalcoholic fatty liver disease Core tip: The Src homology 2B (SH2B) family members mediate cell signaling in response to a variety of hormones, cytokines, and growth factors. In the brain, SH2B1 enhances leptin signaling and leptin's antiobesity action. In peripheral tissues, SH2B1 cell-autonomously enhances insulin signaling. In pancreatic islets, SH2B1 is required for compensatory β cell expansion in response to insulin resistance and β cell stress. SH2B1-deficiency results in severe leptin resistance, energy imbalance, obesity, and type 2 diabetes. SH2B1 mutations are linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Thus, SH2B1 is a critical metabolic regulator in mammals.Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5(4): 511-526 Available from:

show abstract

“…The C-terminal tail has SH3sites that recruit Dock to direct axon guidance, and SH2-sites that recruit Chico to regulate growth (89). At the InR N-terminal juxtamembrane domain, SH2B sites recruit Lnk to modulate interaction with Chico, and mutation of lnk extends lifespan (90)(91)(92)(93). Based on these facts, we…”

Section: Inr 353(hr) : Kinase Insert Domainmentioning

confidence: 92%

MappingDrosophilainsulin receptor structure to the regulation of aging through analysis of amino acid substitutions

Yamamoto

Palmer

Koski

et al. 2020

Preprint

View full text Add to dashboard Cite

ABSTRACTGenetic manipulations of the Drosophila insulin/IGF signaling system slow aging, but it remains unknown how the insulin/IGF receptor acts to modulate lifespan or differentiate this control from that of growth, reproduction and metabolism. With homologous recombination we produced an allelic series of single amino acid substitutions in the fly insulin receptor (InR). Based on emerging biochemical and structural data, we map amino acid substitutions to receptor function to longevity and fecundity. We propose InR mutants generate bias in the process of asymmetric transphosphorylation when the receptor is activated. This induces specific kinase subdomains that modulate lifespan by additive processes, one involving survival costs of reproduction and the other involving reproduction-independent systems of longevity assurance. We identify a mutant in the kinase insert domain that robustly extends lifespan without affecting growth or reproduction, suggesting this element controls aging through unique mechanisms of longevity assurance.

show abstract

The Lnk/SH2B adaptor provides a fail-safe mechanism to establish the Insulin receptor-Chico interaction

Cited by 26 publications

References 35 publications

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

SH2B1 regulation of energy balance, body weight, and glucose metabolism

MappingDrosophilainsulin receptor structure to the regulation of aging through analysis of amino acid substitutions

Contact Info

Product

Resources

About