The Nck-interacting Kinase (NIK) Phosphorylates the Na+-H+ Exchanger NHE1 and Regulates NHE1 Activation by Platelet-derived Growth Factor

Wang, Yan; Nehrke, Keith; Choi, Jimmy C.S.; Barber, Diane L.

doi:10.1074/jbc.m102679200

Cited by 99 publications

(101 citation statements)

References 49 publications

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“…2B). As a positive control we confirmed that NIK phosphorylated a GST fusion of the C terminus of the Na-H exchanger NHE1, as described (24) (Fig. 2B).…”

Section: Nik Activity Is Necessary For Lamellipodium Extension By Egfmentioning

confidence: 57%

“…Although STAT3 coprecipitates with HGK, its direct phosphorylation is undetermined. In mammalian fibroblasts NIK binds to the Na-H exchanger NHE1 and directly phosphorylates NHE1 to increase H ϩ efflux in response to PDGF (24). ERM proteins also bind to NHE1 (33), and by anchoring actin filaments ERM proteins maintain the localization of NHE1 at the leading edge of migrating fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…To further confirm the action and specificity of NIK activity we examined the kinetics of phosphorylation of the conserved threonine in ERM proteins in CCL39 fibroblasts, which express receptors for PDGF and thrombin (24). PDGF induced a rapid increase in the abundance of pERM proteins in CCL39 cells infected with control Ad (Fig.…”

Section: Nik Activity Is Necessary For Phosphorylation Of Erm Proteinmentioning

confidence: 99%

“…Because NIK acts downstream of receptor tyrosine kinases (23,24), we asked whether its kinase activity regulates dynamic changes in cell morphology in response to growth factors. In rat mammary epithelial MTLn3 cells, which extend broad lamellipodia with addition of EGF (25), NIK activity was necessary for increased membrane protrusion by EGF.…”

Section: Nik Activity Is Necessary For Lamellipodium Extension By Egfmentioning

confidence: 99%

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The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

Baumgärtner

Sillman²,

Blackwood³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian Ste20-like Nck-interacting kinase (NIK) and its orthologs Misshapen in Drosophila and Mig-15 in Caenorhabditis elegans have a conserved function in regulating cell morphology, although through poorly understood mechanisms. We report two previously unrecognized actions of NIK: regulation of lamellipodium formation by growth factors and phosphorylation of the ERM proteins ezrin, radixin, and moesin. ERM proteins regulate cell morphology and plasma membrane dynamics by reversibly anchoring actin filaments to integral plasma membrane proteins. In vitro assays show that NIK interacts directly with ERM proteins, binding their N termini and phosphorylating a conserved C-terminal threonine. In cells, NIK and phosphorylated ERM proteins localize at the distal margins of lamellipodia, and NIK activity is necessary for phosphorylation of ERM proteins induced by EGF and PDGF, but not by thrombin. Lamellipodium extension in response to growth factors is inhibited in cells expressing a kinase-inactive NIK, suppressed for NIK expression with siRNA oligonucleotides, or expressing ezrin T567A that cannot be phosphorylated. These data suggest that direct phosphorylation of ERM proteins by NIK constitutes a signaling mechanism controlling growth factor-induced membrane protrusion and cell morphology.ezrin ͉ moesin ͉ ste20 kinase ͉ membrane protrusion T he Nck-interacting kinase (NIK) is a member of the germinal center kinase subfamily of Ste20͞MAP4K serine͞threonine kinases (1). Closely related to NIK are the mammalian kinases TNIK (2), MINK (3), and NRK͞NESK (4) and orthologs Misshapen (Msn) in Drosophila (5) and MIG-15 in Caenorhabditis elegans (6). NIK and its orthologs share a common function in regulating cell shape and migration. In mice, homozygous knockout of NIK results in early embryonic lethality with defects in mesoderm migration (7), and expression of kinase-inactive NIK attenuates epithelial cell invasion (8). Msn functions in determining epithelial polarity, dorsal closure. and neuronal targeting (5, 9, 10), and MIG-15 controls axonal navigation (6). NIK (1) and Msn (5) also share a conserved activation of the JNK pathway. NIK, however, does not directly phosphorylate JNK, nor do NIK nullizygous embryos precisely phenocopy mice lacking JNK1 or JNK2 (7). Additionally, activation of JNK is not associated with dynamic changes in cell morphology. Hence, NIK substrates that control cell morphogenesis have not been identified.We now report that the ERM proteins ezrin, radixin, and moesin are substrates for NIK. ERM proteins regulate cell morphology by cross-linking actin filaments to the plasma membrane. The N-terminal FERM (4.1 ERM) domain of ERM proteins binds to integral plasma membrane proteins and the C terminus binds F-actin (11). ERM proteins control cell shape primarily by regulating membrane protrusions and cell-substrate adhesion. In epithelial cells ERM proteins are necessary for the formation of apical microvilli (12)(13)(14). In fibroblasts ERM proteins regulate the assembly of focal adhesions (...

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“…2B). As a positive control we confirmed that NIK phosphorylated a GST fusion of the C terminus of the Na-H exchanger NHE1, as described (24) (Fig. 2B).…”

Section: Nik Activity Is Necessary For Lamellipodium Extension By Egfmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Nik Activity Is Necessary For Phosphorylation Of Erm Proteinmentioning

confidence: 99%

Section: Nik Activity Is Necessary For Lamellipodium Extension By Egfmentioning

confidence: 99%

See 2 more Smart Citations

The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

Baumgärtner

Sillman²,

Blackwood³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

127

150

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show abstract

“…Regulation of NHE1 by these stimuli has been reported to occur through a variety of signaling molecules, i.e. calcinuerin B homologous protein (6,7), Ca 2ϩ /calmodulin (8,9), low molecular mass GTPases Ras and Rho (10 -12), p42/44 mitogen-activated protein kinases (13), p90 ribosomal S6 kinase (14), 14-3-3 protein (15), Nck-interacting kinase (16), and phosphatidylinositol 4,5-bisphosphate (17). However, the interrelationship of these signaling molecules and the mechanism by which they modulate the interaction of the putative H ϩ modifier site with intracellular protons is still unclear.…”

mentioning

confidence: 99%

Mutations of Arg440 and Gly455/Gly456 Oppositely Change pH Sensing of Na+/H+ Exchanger 1

Wakabayashi

Hisamitsu

Pang

et al. 2003

Journal of Biological Chemistry

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To identify important amino acid residues involved in intracellular pH (pH i ) sensing of Na ؉ /H ؉ exchanger 1, we produced single-residue substitution mutants in the region of the exchanger encompassing the putative 11th transmembrane segment (TM11) and its adjacent intracellular (intracellular loop (IL) 5) and extracellular loops (extracellular loop 6). Substitution of Arg 440 in IL5 with other residues except positively charged Lys caused a large shift in pH i dependence of 22 Na ؉ uptake to an acidic side, whereas substitution of Gly 455 or Gly 456 within the highly conserved glycine-rich sequence of TM11 shifted pH i dependence to an alkaline side. The observed alkaline shift was larger with substitution of Gly 455 with residues with increasing sizes, suggesting the involvement of the steric effect. Interestingly, mutation of Arg 440 (R440D) abolished the ATP depletion-induced acidic shift in pH i dependence of 22 Na ؉ uptake as well as the cytoplasmic alkalinization induced by various extracellular stimuli, whereas with that of Gly 455 (G455Q) these functions were preserved. These mutant exchangers did not alter apparent affinities for extracellular transport substrates Na ؉ and H ؉ and the inhibitor 5-(N-ethyl-N-isopropyl)amiloride. These results suggest that positive charge at Arg 440 is required for normal pH i sensing, whereas mutation-induced perturbation of the TM11 structure may be involved in the effects of Gly mutations. Thus, both Arg 440 in IL5 and Gly residues in the conserved segment of TM11 appear to constitute important elements for proper functioning of the putative "pH i sensor" of Na ؉ /H ؉ exchanger 1.

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Roles of Ion Transport in Control of Cell Motility

Stock

Ludwig

Hanley

et al. 2013

Comprehensive Physiology

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Cell motility is an essential feature of life. It is essential for reproduction, propagation, embryonic development, and healing processes such as wound closure and a successful immune defense. If out of control, cell motility can become life-threatening as, for example, in metastasis or autoimmune diseases. Regardless of whether ciliary/flagellar or amoeboid movement, controlled motility always requires a concerted action of ion channels and transporters, cytoskeletal elements, and signaling cascades. Ion transport across the plasma membrane contributes to cell motility by affecting the membrane potential and voltage-sensitive ion channels, by inducing local volume changes with the help of aquaporins and by modulating cytosolic Ca(2+) and H(+) concentrations. Voltage-sensitive ion channels serve as voltage detectors in electric fields thus enabling galvanotaxis; local swelling facilitates the outgrowth of protrusions at the leading edge while local shrinkage accompanies the retraction of the cell rear; the cytosolic Ca(2+) concentration exerts its main effect on cytoskeletal dynamics via motor proteins such as myosin or dynein; and both, the intracellular and the extracellular H(+) concentration modulate cell migration and adhesion by tuning the activity of enzymes and signaling molecules in the cytosol as well as the activation state of adhesion molecules at the cell surface. In addition to the actual process of ion transport, both, channels and transporters contribute to cell migration by being part of focal adhesion complexes and/or physically interacting with components of the cytoskeleton. The present article provides an overview of how the numerous ion-transport mechanisms contribute to the various modes of cell motility.

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The Nck-interacting Kinase (NIK) Phosphorylates the Na+-H+ Exchanger NHE1 and Regulates NHE1 Activation by Platelet-derived Growth Factor

Cited by 99 publications

References 49 publications

The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

Mutations of Arg440 and Gly455/Gly456 Oppositely Change pH Sensing of Na+/H+ Exchanger 1

Roles of Ion Transport in Control of Cell Motility

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