Insulin-like Growth Factor-I-stimulated Insulin Receptor Substrate-1 Negatively Regulates Src Homology 2 Domain-containing Protein-tyrosine Phosphatase Substrate-1 Function in Vascular Smooth Muscle Cells

Radhakrishnan, Yashwanth; Busby, Walker H.; Shen, Xinchun; Maile, Laura A.; Clemmons, David R.

doi:10.1074/jbc.m109.092270

Cited by 23 publications

(26 citation statements)

References 73 publications

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“…In addition, IRS-1-mediated recruitment or sequestration of protein tyrosine phosphatase (SHP-2) upon IGF-I stimulation results in the blockade of extracellular signal-regulated kinase (ERK)-mediated VSMC proliferation (24,46). Thus, sitespecific IRS-1 tyrosine phosphorylation and IRS-1/SHP-2 interaction promote the contractile phenotype while opposing the proliferative phenotype in VSMCs (24,46).…”

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confidence: 94%

“…Of importance, PDGF has the ability to induce phenotypic switching in VSMCs from the contractile state to the proliferative state, and this has been attributed to the unique property of phenotypic plasticity in VSMCs (41). Studies by several investigators suggest that VSMC phenotypic switching is also determined by the phosphorylation state or the expression levels of insulin receptor substrate (IRS) (23,24,36,37,46,64), a key intermediary component that is shared by insulin and insulin-like growth factor I (IGF-I) receptor signaling. To date, the role of PDGF on insulin receptor signaling components has not been examined in VSMCs.…”

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confidence: 99%

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PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

Zhao

Biswas

McNulty

et al. 2011

American Journal of Physiology-Cell Physiology

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In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS-2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states.

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confidence: 94%

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confidence: 99%

PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

Zhao

Biswas

McNulty

et al. 2011

American Journal of Physiology-Cell Physiology

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“…Control culture showed that PQ401 was functioning to inhibit IGF-I receptor autophosphorylation (Fig. 2F) (39).…”

Section: Fig 2 Knockdown Of Igfbp-2 Suppresses Rptp␤ Dimerization Andmentioning

confidence: 99%

Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling

Shen

Maile

et al. 2012

Molecular and Cellular Biology

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“…SHPS-1 (SH2 domain-containing protein tyrosine phosphatase substrate 1) is an integral membrane protein that acts as a scaffold for multiprotein signaling complexes that are assembled in response to IGF-I in vascular smooth muscle cells or endothelial cells in response to hyperglycemia. The SHPS-1 cytoplasmic domain (SHPS-1/CD) contains four tyrosines that are phosphorylated by the IGF-I receptor (22). This leads to recruitment of the SH2 domain containing phosphatase SHP2.…”

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confidence: 99%

PDK1 Recruitment to the SHPS-1 Signaling Complex Enhances Insulin-like Growth Factor-I-stimulated AKT Activation and Vascular Smooth Muscle Cell Survival

Shen

Radhakrishnan

et al. 2010

Journal of Biological Chemistry

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In vascular smooth muscle cells, exposed to hyperglycemia and insulin-like growth factor-I (IGF-I), SHPS-1 functions as a scaffold protein, and a signaling complex is assembled that leads to AKT activation. However, the underlying mechanism by which formation of this complex activates the kinase that phosphorylates AKT (Thr 308 ) is unknown. Therefore, we investigated the mechanism of PDK1 recruitment to the SHPS-1 signaling complex and the consequences of disrupting PDK1 recruitment for downstream signaling. Our results show that following IGF-I stimulation, PDK1 is recruited to SHPS-1, and its recruitment is mediated by Grb2, which associates with SHPS-1 via its interaction with Pyk2, a component of the SHPS-1-associated complex. A proline-rich sequence in PDK1 bound to an Src homology 3 domain in Grb2 in response to IGF-I. Disruption of Grb2-PDK1 by expression of either a Grb2 Src homology 3 domain or a PDK1 proline to alanine mutant inhibited PDK1 recruitment to SHPS-1, leading to impaired IGF-Istimulated AKT Thr 308 phosphorylation. Following its recruitment to SHPS-1, PDK1 was further activated via Tyr 373/376 phosphorylation, and this was required for a maximal increase in PDK1 kinase activity and AKT-mediated FOXO3a Thr 32 phosphorylation. PDK1 recruitment was also required for IGF-I to prevent apoptosis that occurred in response to hyperglycemia. Assembly of the Grb2-PDK1 complex on SHPS-1 was specific for IGF-I signaling because inhibiting PDK1 recruitment to SHPS-1 had no effect on EGF-stimulated AKT Thr 308 phosphorylation. These findings reveal a novel mechanism for recruitment of PDK1 to the SHPS-1 signaling complex, which is required for IGF-I-stimulated AKT Thr 308 phosphorylation and inhibition of apoptosis.AKT is phosphorylated at two key regulatory sites, Thr 308 in the activation loop of the catalytic domain and Ser 473 in the COOH-terminal domain. PDK1 (3-phosphoinositidedependent kinase 1) is the kinase responsible for phosphorylation of Thr 308 (1), and this is required for AKT-mediated inhibition of apoptosis (2-5). Although constitutive autophosphorylation of PDK1 Ser 241 is required for PDK1 kinase activity, it is not regulated by growth factors (1, 6). However, PDK1 activity is regulated by changes in its conformation, tyrosine phosphorylation, and subcellular localization (7-12). PDK1 undergoes tyrosine phosphorylation in response to insulin, angiotensin II, high glucose, and insulin-like growth factor-I (IGF-I) 2 (9,(11)(12)(13)(14)(15)(16)(17). Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr 373/376 (11,12,14,17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr 9 and then Tyr 373/376 (14, 17). A previous study suggested that Pyk2 (proline-rich tyrosine kinase 2) plays an important role in PDK1 activation. Tanniyama et al. (9) showed that Pyk2 was required for optimal PDK1 tyrosine phosphorylation in response to angiotensin II and that Pyk2 and PDK1 were co...

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Insulin-like Growth Factor-I-stimulated Insulin Receptor Substrate-1 Negatively Regulates Src Homology 2 Domain-containing Protein-tyrosine Phosphatase Substrate-1 Function in Vascular Smooth Muscle Cells

Cited by 23 publications

References 73 publications

PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling

PDK1 Recruitment to the SHPS-1 Signaling Complex Enhances Insulin-like Growth Factor-I-stimulated AKT Activation and Vascular Smooth Muscle Cell Survival

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