Mechanism of Ca2+-mediated Regulation of NDR Protein Kinase through Autophosphorylation and Phosphorylation by an Upstream Kinase

Tamaskovic, Rastislav; Bichsel, Samuel J.; Rogniaux, Hélène; Stegert, Mario; Hemmings, Brian A.

doi:10.1074/jbc.m210590200

Cited by 85 publications

(143 citation statements)

References 47 publications

(49 reference statements)

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“…5B). This suggests that NDR2 activation by Ca 2ϩ / S100B also occurs by the mechanism reported for NDR1 (9,11). After in vitro incubation of GST-NDR2 in the presence and absence of Ca 2ϩ /S100B, the proteins were digested with trypsin and the resultant mixture analyzed by electrospray ionizationtandem mass spectrometry in a Ϫ79 precursor scan (18).…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial Expression and Kinase Assay of Human GST-fused NDR2-Expression of pGEX-2T_NDR2 species in the BL21-DE3 (pRep4) Escherichia coli strain and in vitro kinase assays (autophosphorylation in presence or absence of 100 M CaCl 2 and 10 M bovine S100B (Sigma)) were performed as described previously for NDR1 (11).…”

Section: Methodsmentioning

confidence: 99%

“…Western Blotting-Immunodetection of NDR2 phosphorylated on Thr-75, Ser-282, or Thr-442 was as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

“…The human NDR1 protein has been shown to become autophosphorylated on Ser-281 and activated upon S100B binding in a Ca 2ϩ -dependent manner. The C-terminal regulatory phosphorylation site Thr-444 is phosphorylated in vivo by a so far unidentified upstream kinase (11). This phosphorylation within the hydrophobic motif, which is an event typical of the regulation of many AGC group kinases, promotes kinase activation and protein stability (12,13).…”

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confidence: 99%

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Regulation of NDR2 Protein Kinase by Multi-site Phosphorylation and the S100B Calcium-binding Protein

Stegert¹,

Tamaskovic²,

Bichsel³

et al. 2004

Journal of Biological Chemistry

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Nuclear Dbf2-related (NDR) protein kinases are a family of AGC group kinases that are involved in the regulation of cell division and cell morphology. We describe the cloning and characterization of the human and mouse NDR2, a second mammalian isoform of NDR protein kinase. NDR1 and NDR2 share 86% amino acid identity and are highly conserved between human and mouse. However, they differ in expression pattern; mouse Ndr1 is expressed mainly in spleen, lung and thymus, whereas mouse Ndr2 shows highest expression in the gastrointestinal tract. NDR2 is potently activated in cells following treatment with the protein phosphatase 2A inhibitor okadaic acid, which also results in phosphorylation on the activation segment residue Ser-282 and the hydrophobic motif residue Thr-442. We show that Ser-282 becomes autophosphorylated in vivo, whereas Thr-442 is targeted by an upstream kinase. This phosphorylation can be mimicked by replacing the hydrophobic motif of NDR2 with a PRK2-derived sequence, resulting in a constitutively active kinase. Similar to NDR1, the autophosphorylation of NDR2 protein kinase was stimulated in vitro by S100B, an EF-hand Ca 2؉ -binding protein of the S100 family, suggesting that the two isoforms are regulated by the same mechanisms. Further we show a predominant cytoplasmic localization of ectopically expressed NDR2.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Western Blotting-Immunodetection of NDR2 phosphorylated on Thr-75, Ser-282, or Thr-442 was as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of NDR2 Protein Kinase by Multi-site Phosphorylation and the S100B Calcium-binding Protein

Stegert¹,

Tamaskovic²,

Bichsel³

et al. 2004

Journal of Biological Chemistry

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“…The phosphorylation of the activation segment site Ser-281 and the hydrophobic motif site Thr-444 of Ndr increase Ndr kinase activity in vitro (Millward et al, 1999). Ser-281 phosphorylation is thought to be due to autophosphorylation, whereas Thr-444 is targeted by an as yet unidentified upstream kinase (Tamaskovic et al, 2003;Stegert et al, 2004). These sites are also important regulatory sites for Trc function in the Drosophila epidermis and nervous system.…”

Section: Introductionmentioning

confidence: 99%

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

Emoto

Fang

et al. 2005

MBoC

127

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The function of Tricornered (Trc), the Drosophila Ndr (Nuclear Dbf2-related) serine/threonine protein kinase, is required for the normal morphogenesis of a variety of polarized outgrowths including epidermal hairs, bristles, arista laterals, and dendrites. In yeast the Trc homolog Cbk1 needs to bind Mob2 to activate the RAM pathway. In this report, we provide genetic and biochemical data that Drosophila Trc also interacts with and is activated by Drosophila Dmob proteins. In addition, Drosophila Mob proteins appear to interact with the related Warts/Lats kinase, which functions as a tumor suppressor in flies and mammals. Interestingly, the overgrowth tumor phenotype that results from mutations in Dmob1 (mats) was only seen in genetic mosaics and not when the entire animal was mutant. We conclude that unlike in yeast, in Drosophila individual Mob proteins interact with multiple kinases and that individual NDR family kinases interact with multiple Mob proteins. We further provide evidence that Mo25, the Drosophila homolog of the RAM pathway hym1 gene does not function along with Trc.

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NDR1/STK38 potentiates NF‐κB activation by its kinase activity

Shi

Lü

et al. 2012

Cell Biochemistry & Function

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Human NDR1/STK38 belongs to the nuclear-Dbf2-related (NDR) family of Ser/Thr kinases. It has been implicated to function in centrosome duplication, control of cell cycle and apoptosis. However, the mechanism of NDR1 signaling pathway remains largely elusive. Here, we report a novel role of NDR1 in NF-κB activation. By overexpression, NDR1 potentiates NF-κB activation induced by TNFα, whereas knockdown of NDR1 expression inhibits NF-κB activation induced by TNFα. Coimmunoprecipitation shows that NDR1 interacts with multiple signal components except p65 in NF-κB signaling pathway. Furthermore, both phosphorylation and kinase dead mutants of NDR1 lose their synergistic effects on TNFα-induced NF-κB activation. siRNA oligo against NDR1 and kinase dead mutant as well mainly block the NF-κB activation induced by TRAF2 but not RIP1. Furthermore, kinase dead mutant of NDR1 fails to interact with TRAF2. Taken together, our findings suggest an unknown function of NDR1, which may regulate NF-κB activation by its kinase activity.

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Mechanism of Ca2+-mediated Regulation of NDR Protein Kinase through Autophosphorylation and Phosphorylation by an Upstream Kinase

Cited by 85 publications

References 47 publications

Regulation of NDR2 Protein Kinase by Multi-site Phosphorylation and the S100B Calcium-binding Protein

Regulation of NDR2 Protein Kinase by Multi-site Phosphorylation and the S100B Calcium-binding Protein

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

NDR1/STK38 potentiates NF‐κB activation by its kinase activity

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