Identification of SH2B1β as a focal adhesion protein that regulates focal adhesion size and number

Lanning, Nathan; Su, Hsiao Wen; Argetsinger, Lawrence S.; Carter‐Su, Christin

doi:10.1242/jcs.081547

Cited by 16 publications

(23 citation statements)

References 63 publications

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“…We showed previously that SH2B1b co-localizes with vinculin, FAK, and at the tips of actin filaments at focal adhesions (Lanning et al, 2011). We therefore determined whether mutating Tyr439 and Tyr494 in SH2B1b affects SH2B1b localization to focal adhesions.…”

Section: Tyr439 and Tyr494 Do Not Contribute To Basal Cycling Of Sh2bmentioning

confidence: 93%

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Phosphorylation of the adaptor protein SH2B1βregulates its ability to enhance growth hormone (GH)-dependent macrophage motility

Lanning

Morris

et al. 2013

Journal of Cell Science

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SummaryPrevious studies have shown that growth hormone (GH) recruits the adapter protein SH2B1b to the GH-activated, GH receptorassociated tyrosine kinase JAK2, implicating SH2B1b in GH-dependent actin cytoskeleton remodeling, and suggesting that phosphorylation at serines 161 and 165 in SH2B1b releases SH2B1b from the plasma membrane. Here, we examined the role of SH2B1b in GH regulation of macrophage migration. We show that GH stimulates migration of cultured RAW264.7 macrophages, and primary cultures of peritoneal and bone marrow-derived macrophages. SH2B1b overexpression enhances, whereas SH2B1 knockdown inhibits, GH-dependent motility of RAW macrophages. At least two independent mechanisms regulate the SH2B1b-mediated changes in motility. In response to GH, tyrosines 439 and 494 in SH2B1b are phosphorylated. Mutating these tyrosines in SH2B1b decreases both basal and GH-stimulated macrophage migration. In addition, mutating the polybasic nuclear localization sequence (NLS) in SH2B1b or creating the phosphomimetics SH2B1b(S161E) or SH2B1b(S165E), all of which release SH2B1b from the plasma membrane, enhances macrophage motility. Conversely, SH2B1b(S161/165A) exhibits increased localization at the plasma membrane and decreased macrophage migration. Mutating the NLS or the nearby serine residues does not alter GH-dependent phosphorylation on tyrosines 439 and 494 in SH2B1b. Mutating tyrosines 439 and 494 does not affect localization of SH2B1b at the plasma membrane or movement of SH2B1b into focal adhesions. Taken together, these results suggest that SH2B1b enhances GH-stimulated macrophage motility via mechanisms involving phosphorylation of SH2B1b on tyrosines 439 and 494 and movement of SH2B1b out of the plasma membrane (e.g. as a result of phosphorylation of serines 161 and 165).

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Section: Tyr439 and Tyr494 Do Not Contribute To Basal Cycling Of Sh2bmentioning

confidence: 93%

“…8B,C). This is in contrast to mutating Ser161 and Ser165 to Ala, which substantially decreases dynamic cycling of SH2B1b into and out of focal adhesions (Lanning et al, 2011).…”

Section: Tyr439 and Tyr494 Do Not Contribute To Basal Cycling Of Sh2bmentioning

confidence: 96%

Phosphorylation of the adaptor protein SH2B1βregulates its ability to enhance growth hormone (GH)-dependent macrophage motility

Lanning

Morris

et al. 2013

Journal of Cell Science

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“…SH2B1 mediates GH regulation of cell adhesion and migration. GH increases the cycling of SH2B1 into and out of focal adhesions [26] , and promotes SH2B1 colocalization with F-actin in membrane ruffles [66] . 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] .…”

Section: Sh2b1 Regulates Multiple Cellular Responsesmentioning

confidence: 98%

“…NGF stimulates SH2B1 phosphorylation on multiple Ser/Thr residues [21] . Mitogen-activated protein kinase (MAPK) directly phosphorylates Ser 96 [21] , and protein kinase C phosphorylates both Ser 161 and Ser 165 residues [22,26] . However, the physiological consequence of SH2B1 phosphorylation remains unknown.…”

Section: Metabolic Function Of Sh2b1mentioning

confidence: 99%

“…SH2B1 regulates actin cytoskeletal reorganization and cell motility: SH2B1 is able to regulate cell morphology, adhesion, and motility through modifying actin cytoskeletal reorganization in cultured cells. SH2B1β is detected in membrane ruffles, filopodia, and focal adhesions [26,59] , and is colocalizated with filamentous actin (Factin) in membrane ruffles [66] . SH2B1β binds via both its N-terminal (amino acids 150-200) and C-terminal regions (amino acids 615-670) to F-actin, and promotes actin filament cross-link [59] .…”

Section: Sh2b1 Regulates Multiple Cellular Responsesmentioning

confidence: 99%

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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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SH2B1 promotes epithelial‐mesenchymal transition through the IRS1/β‐catenin signaling axis in lung adenocarcinoma

Wang

Cheng

Gao

et al. 2018

Molecular Carcinogenesis

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Lung adenocarcinoma (LADC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2‐domain containing family, have recently been shown to act as tumor activators in multiple cancers, including LADC. However, the mechanisms underlying SH2B1 overexpression are not completely understood. Here, we reported that SH2B1 expression levels were significantly upregulated and positively associated with EMT markers and poor patient survival in LADC specimens. Modulation of SH2B1 levels had distinct effects on cell proliferation, cell cycle, migration, invasion, and morphology in A549 and H1299 cells in vitro and in vivo. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the EMT markers, especially induced β‐catenin accumulation and activated β‐catenin signaling to promote LADC cell proliferation and metastasis, while silencing SH2B1 had the opposite effect. Furthermore, ectopic expression of SH2B1 in H1299 cells increased IRS1 expression level. Reduced expression of IRS1 considerably inhibited H1299 cell proliferation, migration, and invasion which were driven by SH2B1 overexpression. Collectively, these results provide unequivocal evidence to establish that SH2B1‐IRS1‐β‐catenin axis is required for promoting EMT, and might prove to be a promising strategy for restraining tumor progression in LADC patients.

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Identification of SH2B1β as a focal adhesion protein that regulates focal adhesion size and number

Cited by 16 publications

References 63 publications

Phosphorylation of the adaptor protein SH2B1βregulates its ability to enhance growth hormone (GH)-dependent macrophage motility

Phosphorylation of the adaptor protein SH2B1βregulates its ability to enhance growth hormone (GH)-dependent macrophage motility

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

SH2B1 promotes epithelial‐mesenchymal transition through the IRS1/β‐catenin signaling axis in lung adenocarcinoma

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