GSK3 at the Edge: Regulation of Developmental Specification and Cell Polarization

Kim, Leung; Kimmel, Alan R.

doi:10.2174/1389450110607011411

Cited by 38 publications

(29 citation statements)

References 7 publications

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“…Conversely, in neurospheres, the inhibition of GSK3␤ results in increased differentiation of neuronal precursors into dopaminergic neurons (48). Partial or complete knock-down of GSK3␤ by shRNA in cultured neurons and tissue slices (49) showed that inactivation of GSK3␤ at neurite tips leads to axon elongation, whereas reduction of GSK3␤ throughout the neuron causes axon branching, and strong suppression of GSK3␤ results in termination of axon growth.…”

Section: Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2

Timm¹,

Balusamy²,

et al. 2008

Journal of Biological Chemistry

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MARK/Par-1, a kinase family with diverse functions particularly in inducing cell polarity, can phosphorylate microtubule-associated proteins in their repeat domain and cause their detachment from microtubules, and thereby microtubule destabilization. Because of its role in abnormal phosphorylation of the Tau protein in Alzheimer disease, we searched for regulatory kinases. MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3␤ serves the role of the inhibitory kinase. Because GSK3␤ can also phosphorylate Tau at sites outside the repeat domain, the activation of GSK3␤, and concomitant inactivation of MARK can shift the pattern of pathological phosphorylation of Tau protein in Alzheimer disease.

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Section: Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2

Timm¹,

Balusamy²,

et al. 2008

Journal of Biological Chemistry

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“…GSK-3␤ has a wide range of functions in higher eukaryotes, including the establishment of cell polarity (Kim and Kimmel, 2006). Notably, in the Hedgehog and the canonical Wnt pathway, GSK-3␤ mediates degradation of a transcription factor through phosphorylation of these proteins (Kim and Kimmel, 2006). Together, we propose a model, in which Rdi1 and Ygk3 coordinately regulate Rho4 degradation by vacuolar proteases and the proteasome (Figure 10).…”

Section: Degradation Of Rho4mentioning

confidence: 92%

“…It is one of four yeast homologues of GSK-3␤, and it probably has a role in ubiquitin-dependent protein degradation (Andoh et al, 2000;Kassir et al, 2006). GSK-3␤ has a wide range of functions in higher eukaryotes, including the establishment of cell polarity (Kim and Kimmel, 2006). Notably, in the Hedgehog and the canonical Wnt pathway, GSK-3␤ mediates degradation of a transcription factor through phosphorylation of these proteins (Kim and Kimmel, 2006).…”

Section: Degradation Of Rho4mentioning

confidence: 99%

The Rho GDI Rdi1 Regulates Rho GTPases by Distinct Mechanisms

Tiedje

Sakwa

Just

et al. 2008

MBoC

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The small guanosine triphosphate (GTP)-binding proteins of the Rho family are implicated in various cell functions, including establishment and maintenance of cell polarity. Activity of Rho guanosine triphosphatases (GTPases) is not only regulated by guanine nucleotide exchange factors and GTPase-activating proteins but also by guanine nucleotide dissociation inhibitors (GDIs). These proteins have the ability to extract Rho proteins from membranes and keep them in an inactive cytosolic complex. Here, we show that Rdi1, the sole Rho GDI of the yeast Saccharomyces cerevisiae, contributes to pseudohyphal growth and mitotic exit. Rdi1 interacts only with Cdc42, Rho1, and Rho4, and it regulates these Rho GTPases by distinct mechanisms. Binding between Rdi1 and Cdc42 as well as Rho1 is modulated by the Cdc42 effector and p21-activated kinase Cla4. After membrane extraction mediated by Rdi1, Rho4 is degraded by a novel mechanism, which includes the glycogen synthase kinase 3␤ homologue Ygk3, vacuolar proteases, and the proteasome. Together, these results indicate that Rdi1 uses distinct modes of regulation for different Rho GTPases. INTRODUCTIONSmall guanosine triphosphatases (GTPases) of the Rho family control fundamental processes of cell biology common to all eukaryotes, such as morphogenesis, polarity, movement, and cell division (Jaffe and Hall, 2005). In the budding yeast Saccharomyces cerevisiae, which encodes six Rho GTPases (Cdc42 and Rho1 to Rho5), these proteins play a pivotal role in the establishment of cell polarity (Park and Bi, 2007). Budding yeast cells undergo polarized growth during various phases of their life cycle, including budding during vegetative growth, mating between haploid cells of opposite mating types, and filamentous growth upon nutrient limitation. Although Cdc42 and Rho1 are well characterized, little is known about the other Rho proteins. Membrane association of Rho-type GTPases is essential for their function, and it depends on a C-terminal prenyl moiety and an adjacent polybasic region. Cdc42 localizes to internal membranes and the entire plasma membrane, where it clusters at sites of polarized growth, including the tips of mating projections, incipient bud sites, the tips and sides of growing buds, and the bud neck region of large-budded cells (Ziman et al., 1993;Richman et al., 2002). In addition to membranebound Cdc42, a cytoplasmic pool has been found (Ziman et al., 1993). Similar to Cdc42, Rho1 has been shown to localize at sites of polarized growth .Like other regulatory GTPases, they act as molecular switches, cycling between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state. This activity is highly regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The exchange of GDP to GTP, and thus the activation of Cdc42, is catalyzed by GEFs. In the active GTP-bound state, Rho GTPases perform their regulatory function through a conformation-specific interaction with effector proteins. G...

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“…falciparum has two GSK-3-related enzymes (both of which are essential), one of which is found in haemosporidians only (MAL13P1.84), while PfGSK3 (PFC0525c) is shared with other alveolates and metazoans. In humans, GSK3 is a multifunctional kinase affecting a diverse range of cellular functions, including the regulation of metabolism, gene expression, and even cell fate determination and the spatial organization of the embryo [70,71]. The clarification of GSK3's role in insulin regulation in the mid-90's has led to the development of an arsenal of very potent and specific inhibitors with therapeutic potential for the treatment of diabetes [72].…”

Section: The Cmgc Group and Other Cell Cycle Control Kinasesmentioning

confidence: 99%

The kinomes of apicomplexan parasites

Miranda‐Saavedra

Gabaldón

Barton

et al. 2012

Microbes and Infection

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Protein phosphorylation plays a fundamental role in the biology and invasion strategies of apicomplexan parasites. Many apicomplexan protein kinases are substantially different from their mammalian orthologues, and thus constitute a landscape of potential drug targets. Here, we integrate genomic, biochemical, genetic and evolutionary information to provide an integrated and up-to-date analysis of twelve apicomplexan kinomes. All kinome sequences are available through the Kinomer database.2

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GSK3 at the Edge: Regulation of Developmental Specification and Cell Polarization

Cited by 38 publications

References 7 publications

Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2

Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2

The Rho GDI Rdi1 Regulates Rho GTPases by Distinct Mechanisms

The kinomes of apicomplexan parasites

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