Organization of kinases, phosphatases, and receptor signaling complexes

Schillace, Robynn V.; Scott, John D.

doi:10.1172/jci6491

Cited by 93 publications

(51 citation statements)

References 27 publications

(22 reference statements)

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“…Our data suggest that Sur8 plays an important role in the regulation of NPC proliferation and differentiation through the Ras-ERK pathway in response to the growth factors bFGF or EGF. The Scaffold proteins such as Sur8, KSR, and MP1 assemble intracellular signaling complexes and can play important roles in cellular responses [3,[46][47][48]. The scaffold proteins can regulate the efficiency of the signaling response by virtue of their ability to form different complexes with the signaling members of the Ras-ERK pathway such as Ras, Raf [7,49], Erbin, and PP1 [6,49].…”

Section: Discussionmentioning

confidence: 99%

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

Moon

Kim

et al. 2011

Stem Cells

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Sur8/Shoc2 is a scaffold protein that regulates the Rasextracellular signal-regulated kinase (ERK) pathway. However, the roles of Sur8 in cellular physiologies are poorly understood. In this study, Sur8 was severely repressed in the course of neural progenitor cell (NPC) differentiation in the cerebral cortex of developing rat embryos. Similarly, Sur8 was also critically reduced in cultured NPCs, which were induced differentiation by removal of basic fibroblast growth factor (bFGF). Sur8 regulation occurs at the protein level rather than at the mRNA level as revealed by both in situ hybridization and reverse transcriptase polymerase chain reaction analyses. The role of Sur8 in NPC differentiation was confirmed by lentivirus-mediated Sur8 knockdown, which resulted in increased differentiation, whereas exogenous expression of Sur8 inhibited differentiation. Contrastingly, NPC proliferation was promoted by overexpression, but was suppressed by Sur8 knockdown. The role of Sur8 as an antidifferentiation factor in the developing rat brain was confirmed by an ex vivo embryo culture system combined with the lentivirus-mediated Sur8 knockdown. The numbers and sizes of neurospheres were reduced, but neuronal outgrowth was enhanced by the Sur8 knockdown. The Ras-ERK pathway is involved in Sur8-mediated regulations of differentiation, as the treatment of ERK kinase (MEK) inhibitors blocks the effects of Sur8. The regulations of NPCs' differentiation and proliferation by the Ras-ERK pathway were also shown by the rescues of the effects of bFGF depletion, neuronal differentiation, and antiproliferation by epidermal growth factor. In summary, Sur8 is an antidifferentiation factor that stimulates proliferation for maintenance of self-renewal in NPCs via modulation of the Ras-ERK pathway. STEM CELLS 2011; 29:320-331 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionmentioning

confidence: 99%

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

Moon

Kim

et al. 2011

Stem Cells

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“…In many instances substrate specificity is conferred to common catalytic subunits via unique targeting subunits (reviewed in Ref. 39). The targeting subunits are also targets of signaling pathways that may modulate the activity of the enzyme toward its substrate.…”

Section: Discussionmentioning

confidence: 99%

“…The MYPT1 may thus be considered as a scaffold protein, analogous to the cAMP-dependent protein kinase anchoring proteins (reviewed in Ref. 39), that binds a number of proteins that inhibit (Zip-like kinase (13) and CPI-17 (71)) or stimulate (cGKI (this study and Ref. 23)) the activity of the phosphatase and thereby regulate smooth muscle tone.…”

Section: Discussionmentioning

confidence: 99%

Role of Myosin Phosphatase Isoforms in cGMP-mediated Smooth Muscle Relaxation

Khatri¹,

Joyce²,

Brozovich³

et al. 2001

Journal of Biological Chemistry

115

178

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In vitro experiments showing the activation of the myosin phosphatase via heterophilic leucine zipper interactions between its targeting subunit (MYPT1) and cGMP-dependent protein kinase I suggested a pathway for smooth muscle relaxation (Surks, H. K., Mochizuki, N., Kasai, Y., Georgescu, S. P., Tang, K. M., Ito, M., Lincoln, T. M., and Mendelsohn, M. E. (1999) Science 286, 1583-1587). The relationship between MYPT1 isoform expression and smooth muscle responses to cGMP signaling in vivo has not been explored. MYPT1 isoforms that contain or lack a C-terminal leucine zipper are generated in birds and mammals by cassette-type alternative splicing of a 31-nucleotide exon. The avian and mammalian C-terminal isoforms are highly conserved and expressed in a tissue-specific fashion. In the mature chicken the tonic contracting aorta and phasic contracting gizzard exclusively express the leucine zipper positive and negative MYPT1 isoforms, respectively. Expression of the MYPT1 isoforms is also developmentally regulated in the gizzard, which switches from leucine zipper positive to negative isoforms around the time of hatching. This switch coincides with the development in the gizzard of a cGMP-resistant phenotype, i.e. inability to dephosphorylate myosin and relax in response to 8-bromo-cGMP after calcium activation. Furthermore, association of cGMP-dependent protein kinase I with MYPT1 is detected by immunoprecipitation only in the tissue that expresses the leucine zipper positive isoform of MYPT1. These results suggest that the regulated splicing of MYPT1 is an important determinant of smooth muscle phenotypic diversity and the variability in the response of smooth muscles to the calcium desensitizing effect of cGMP signaling.Smooth muscle contraction is initiated by the phosphorylation of the regulatory myosin light chain (MLC 20 ) 1 by the calcium/calmodulin-dependent activation of the myosin light chain kinase (MLCK) (1). Relaxation is effected by the dephosphorylation of MLC 20 by the smooth muscle myosin phosphatase (SMMP). Complexity is brought to this system by accessory proteins and signaling pathways that regulate the smooth muscle contractile state (reviewed in Refs. 2 and 3). The SMMP is a target of signals that are positive and negative modulators of smooth muscle tone. SMMP is a heterotrimeric protein composed of the 37-kDa catalytic subunit (PP1c␦), the 130/133-kDa myosin targeting subunit (MYPT1, also referred to as MBS), and the 21-kDa M21 subunit (4 -6). MYPT1 targets the catalytic subunit to MLC 20 (7,8) and in this way confers substrate specificity to the phosphatase, whereas the function of the M21 subunit is unknown. Activation of the Rho kinase signaling pathway leads to phosphorylation of the MYPT1 subunit, resulting in inhibition of myosin phosphatase activity and an increase in smooth muscle tone (9 -13). This signaling pathway is thought to determine the calcium-sensitizing effect of ␣-adrenergic stimulation, for example, in which greater force is produced at a given calcium concentration th...

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“…Increasingly, novel protein complexes have been identified and characterized to play an important regulatory role in signal transduction in systems involving kinases and phosphatases (19). PTP1B has recently been shown to interact directly with the GRB2 adaptor protein (9).…”

Section: Fig 4 Binding Of Sh2 Domain-containing Adaptor Proteins Tomentioning

confidence: 99%

Tyrosine Dephosphorylation and Deactivation of Insulin Receptor Substrate-1 by Protein-tyrosine Phosphatase 1B

Goldstein

Bittner-Kowalczyk

White

et al. 2000

Journal of Biological Chemistry

373

221

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Regulation of the steady-state tyrosine phosphorylation of the insulin receptor and its postreceptor substrates are essential determinants of insulin signal transduction. However, little is known regarding the molecular interactions that influence the balance of these processes, especially the phosphorylation state of postinsulin receptor substrates, such as insulin receptor substrate-1 (IRS-1). The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. PTP1B exhibited the highest specific activity (percentage dephosphorylated per g per min), and the enzyme activities varied over a range of 5.5 ؋ 10 3 . When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3-kinase paralleled the rate of overall IRS-1 dephosphorylation. Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 ؎ 3.3-fold (n ‫؍‬ 7; p < 0.01). Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. Cellular protein-tyrosine phosphatases (PTPases)1 play a crucial role in maintaining the steady-state phosphotyrosine content of proteins in the insulin action pathway (1, 2). Much of the available evidence characterizing the role of PTPases in insulin signaling has focused on the regulation of the activation state of the insulin receptor itself, where several PTPases, in particular the intracellular enzyme PTP1B and the transmembrane homologs LAR and LRP (RPTP-␣), have been postulated to have a regulatory function (3-6). However, the identity of PTPase(s) that regulate the tyrosine phosphorylation state of substrates of the insulin receptor kinase, such as IRS-1, has not been determined. IRS-1 is phosphorylated on multiple tyrosine residues by the activated insulin receptor kinase and serves as a docking site or scaffold for a series of adaptor proteins that possess Src homology 2 (SH2) domains (7). These proteins bind to specific phosphotyrosine sites on IRS-1, become activated, and transmit the downstream signal from the insulin receptor to various met...

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Organization of kinases, phosphatases, and receptor signaling complexes

Cited by 93 publications

References 27 publications

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

Role of Myosin Phosphatase Isoforms in cGMP-mediated Smooth Muscle Relaxation

Tyrosine Dephosphorylation and Deactivation of Insulin Receptor Substrate-1 by Protein-tyrosine Phosphatase 1B

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