SH2-Bβ Is a Rac-binding Protein That Regulates Cell Motility

Diakonova, Maria; Gunter, David R.; Herrington, James; Carter‐Su, Christin

doi:10.1074/jbc.m111138200

Cited by 55 publications

(60 citation statements)

References 43 publications

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“…Overexpression of SH2B1β, but not SH2 domain-defective SH2B1β(R555E), enhances the ability of GH to stimulate both membrane ruffles in 3T3-F442A fibroblasts [59,66] and macrophage migration [56] . In fact, SH2B1β(R555E) blocks GH-induced lamellipodia dynamics in 3T3-F442A cells [68] . Both the N-terminal region (amino acids and the SH2 domain of SH2B1β are required for GH stimulation of cell motility [68] .…”

Section: Sh2b1 Regulates Multiple Cellular Responsesmentioning

confidence: 94%

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

Rui

2014

WJD

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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:

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Section: Sh2b1 Regulates Multiple Cellular Responsesmentioning

confidence: 94%

“…SH2B1 directly binds via its amino acids 200-260 to the actin-binding protein filamin A [67] . Additionally, SH2B1 binds via its amino acids 85-106 to Rac, a critical regulator of actin cytoskeletal reorganization [68] . SH2B1 mediates GH regulation of cell adhesion and migration.…”

Section: Sh2b1 Regulates Multiple Cellular Responsesmentioning

confidence: 99%

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

Rui

2014

WJD

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“…Phagokinetc Assay-For the phagokinetic assay, HME cells were transfected with cDNA encoding myc-PAK1 T423E, HA-PAK1 WT, HA-PAK1 Y3F, JAK2, or JAK2 K882E as indicated using ExpressFect (Denville Scientific, Inc.) and plated on colloid gold-covered coverslips 48 h after transfection (55,56). Cells remove particles while they move, thereby producing areas that are free of colloid gold.…”

Section: Methodsmentioning

confidence: 99%

JAK2 Tyrosine Kinase Phosphorylates PAK1 and Regulates PAK1 Activity and Functions

Rider

Shatrova

Feener

et al. 2007

Journal of Biological Chemistry

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The serine-threonine kinase PAK1 is activated by small GTPase-dependent and -independent mechanisms and promotes cell survival. However, the role of tyrosyl phosphorylation in the regulation of PAK1 function is poorly understood. In this study, we have shown that the prolactin-activated tyrosine kinase JAK2 phosphorylates PAK1 in vivo. Wild type, but not kinase-dead, JAK2 directly phosphorylates PAK1 in cells and in an in vitro kinase assay. PAK1 tyrosines 153, 201, and 285 were identified as sites of JAK2 tyrosyl phosphorylation by mass spectrometry and two-dimensional peptide mapping. Mutation of PAK1 tyrosines 153, 201, and 285 to phenylalanines individually or in combination implicated these PAK1 tyrosines in the regulation of PAK1 kinase activity. Tyrosyl phosphorylation by JAK2 significantly increases PAK1 kinase activity, whereas similar phosphorylation of the PAK1 Y153F,Y201F,Y285F mutant has no effect on PAK1 activity. Tyrosyl phosphorylation of wild type PAK1 decreases apoptosis induced by serum deprivation and staurosporine treatment and increases cell motility. In contrast, these parameters are unaltered in the PAK1 Y153F,Y201F,Y285F mutant. Our findings indicate that JAK2 phosphorylates PAK1 at these specific tyrosines and that this phosphorylation plays an important role in cell survival and motility. PAK14 is a member of a conserved family of p21-activated serine-threonine kinases and is important for a variety of cellular functions, including cell morphogenesis, motility, survival, mitosis, and malignant transformation (for review see Refs. 1-3). The emerging roles of PAK1 in the regulation of multiple fundamental cellular processes have directed significant attention toward understanding how PAK1 activity is controlled. Autoinhibition of the PAK1 C-terminal catalytic domain by the N-terminal domain is a key mechanism of PAK1 regulation. Several layers of inhibition, involving dimerization and occupation of the catalytic cleft by contact between the Nand C-terminal domains, keep PAK1 kinase activity in check (4). Autoinhibition of PAK1 occurs in trans, meaning that the inhibitory domain of one PAK1 molecule interacts with the kinase domain of another PAK1 molecule (5). Association of GTP-bound forms of Cdc42 and Rac1 with the PAK1 PBD/ CRIB domain induces conformational changes in the N-terminal domain that no longer support its autoinhibitory function. In addition to Cdc42 and Rac1, PAK1 is activated by the binding of small GTPases, Rac2 and Rac3, as well as TC10, CHP, and Wrich-1 proteins (6 -11). PAK1 is a predominantly cytoplasmic protein, but is activated upon recruitment to the cell membrane. PAK1 membrane localization occurs through interaction with adaptor proteins Nck, Grb2, and PIX, all of which are activated by ligation of growth factor receptors (12-15). Membrane recruitment of PAK1 via adapter proteins and subsequent PAK1 activation may involve phosphorylation at Thr 423 (a site that is also autophosphorylated when PAK1 is activated by Rac1 and Cdc42) by PDK1 (16) or interaction with...

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“…In these studies, the dominant active RacL61 construct was used. RacL61 has been used interchangeably with RacV12, and in parallel studies these dominant Rac mutants induce indistinguishable phenotypes (50). In this assay, MG-63 cells were cotransfected with expression constructs at a ratio of 1:3 (PIPKI␣/Rac) and then serum-starved for 20 to 24 h. These cells were stimulated with 10 ng/ml PDGF for 10 min and then stained for actin and PIPKI␣.…”

Section: Fig 5 Pipki␣ Induces Actin Remodeling Dependent Upon Pdgf mentioning

confidence: 99%

Membrane Ruffling Requires Coordination between Type Iα Phosphatidylinositol Phosphate Kinase and Rac Signaling

Doughman

Firestone

Wojtasiak

et al. 2003

Journal of Biological Chemistry

105

104

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Membrane ruffle formation requires remodeling of cortical actin filaments, a process dependent upon the small G-protein Rac. Growth factors stimulate actin remodeling and membrane ruffling by integration of signaling pathways that regulate actin-binding proteins. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) regulates the activity of many actin-binding proteins and is produced by the type I phosphatidylinositol phosphate kinases (PIPKIs). Here we show in MG-63 cells that only the PIPKI␣ isoform is localized to platelet-derived growth factor (PDGF)-induced membrane ruffles. Further, expression of kinase dead PIPKI␣, which acts as a dominant negative mutant, blocked membrane ruffling, suggesting that PIPKI␣ and PIP 2 participate in ruffling. To explore this, PIPKI␣ was overexpressed in serumstarved cells and stimulated with PDGF. In serumstarved cells, PIPKI␣ expression did not stimulate actin remodeling, but when these cells were stimulated with PDGF, actin rapidly reorganized into foci but not membrane ruffles. PIPKI␣-mediated formation of actin foci was independent of both Rac1 and phosphatidylinositol 3-kinase activities. Significantly, coexpression of dominant active Rac1 with PIPKI␣ in PDGF-stimulated cells resulted in membrane ruffling. The PDGF-and Rac1-stimulated ruffling was inhibited by expression of kinase-dead PIPKI␣. Combined, these data support a model where the localized production of PIP 2 by PIPKI␣ is necessary for actin remodeling, whereas formation of membrane ruffles required Rac signaling.

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SH2-Bβ Is a Rac-binding Protein That Regulates Cell Motility

Cited by 55 publications

References 43 publications

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

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

JAK2 Tyrosine Kinase Phosphorylates PAK1 and Regulates PAK1 Activity and Functions

Membrane Ruffling Requires Coordination between Type Iα Phosphatidylinositol Phosphate Kinase and Rac Signaling

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