MEK Kinases Are Regulated by EGF and Selectively Interact with Rac/Cdc42

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1997 Aug 15

PMID 9305638

Citations 92

Authors

G R Fanger

N L Johnson

G L Johnson

Affiliations

Soon will be listed here.

Abstract

MEK kinases (MEKKs) 1, 2, 3 and 4 are members of sequential kinase pathways that regulate MAP kinases including c-Jun NH2-terminal kinases (JNKs) and extracellular regulated kinases (ERKs). Confocal immunofluorescence microscopy of COS cells demonstrated differential MEKK subcellular localization: MEKK1 was nuclear and in post-Golgi vesicular-like structures; MEKK2 and 4 were localized to distinct Golgi-associated vesicles that were dispersed by brefeldin A. MEKK1 and 2 were activated by EGF, and kinase-inactive mutants of each MEKK partially inhibited EGF-stimulated JNK activity. Kinase-inactive MEKK1, but not MEKK2, 3 or 4, strongly inhibited EGF-stimulated ERK activity. In contrast to MEKK2 and 3, MEKK1 and 4 specifically associated with Rac and Cdc42 and kinase-inactive mutants blocked Rac/Cdc42 stimulation of JNK activity. Inhibitory mutants of MEKK1-4 did not affect p21-activated kinase (PAK) activation of JNK, indicating that the PAK-regulated JNK pathway is independent of MEKKs. Thus, in different cellular locations, specific MEKKs are required for the regulation of MAPK family members, and MEKK1 and 4 are involved in the regulation of JNK activation by Rac/Cdc42 independent of PAK. Differential MEKK subcellular distribution and interaction with small GTP-binding proteins provides a mechanism to regulate MAP kinase responses in localized regions of the cell and to different upstream stimuli.

Citing Articles

[Molecular basis of ameloblastoma pathogenesis: A review].

Riofrio Chung G, Santos Tucto T, Quispe-Salcedo A Rev Cient Odontol (Lima). 2024; 12(3):e212.

PMID: 39444727 PMC: 11495173. DOI: 10.21142/2523-2754-1203-2024-212.

MAP3K4 kinase action and dual role in cancer.

Huang Y, Wang G, Zhang N, Zeng X Discov Oncol. 2024; 15(1):99.

PMID: 38568424 PMC: 10992237. DOI: 10.1007/s12672-024-00961-x.

Establishment of a new prognostic risk model of MAPK pathway-related molecules in kidney renal clear cell carcinoma based on genomes and transcriptomes analysis.

Zhang P, Li J, Wang Z, Zhao L, Qiu J, Xu Y Front Oncol. 2023; 13:1077309.

PMID: 36969076 PMC: 10036835. DOI: 10.3389/fonc.2023.1077309.

The gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and mutation results in Hirschsprung's disease.

Bhattarai C, Poudel P, Ghosh A, Kalthur S AIMS Neurosci. 2022; 9(1):128-149.

PMID: 35434281 PMC: 8941195. DOI: 10.3934/Neuroscience.2022008.

Spectrum of mutations in breast cancer is luminal subtype-predominant and related to prognosis.

Li C, Zhang G, Wang Y, Chen B, Li K, Cao L Oncol Lett. 2022; 23(2):68.

PMID: 35069877 PMC: 8756433. DOI: 10.3892/ol.2022.13187.

References

Ishizuka T, Oshiba A, Sakata N, Terada N, Johnson G, Gelfand E . Aggregation of the FcepsilonRI on mast cells stimulates c-Jun amino-terminal kinase activity. A response inhibited by wortmannin. J Biol Chem. 1996; 271(22):12762-6. DOI: 10.1074/jbc.271.22.12762. View

Xu S, Robbins D, Christerson L, ENGLISH J, Vanderbilt C, Cobb M . Cloning of rat MEK kinase 1 cDNA reveals an endogenous membrane-associated 195-kDa protein with a large regulatory domain. Proc Natl Acad Sci U S A. 1996; 93(11):5291-5. PMC: 39238. DOI: 10.1073/pnas.93.11.5291. View

Rana A, Gallo K, Godowski P, Hirai S, Ohno S, Zon L . The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. J Biol Chem. 1996; 271(32):19025-8. DOI: 10.1074/jbc.271.32.19025. View

Teramoto H, Crespo P, Coso O, Igishi T, Xu N, Gutkind J . The small GTP-binding protein rho activates c-Jun N-terminal kinases/stress-activated protein kinases in human kidney 293T cells. Evidence for a Pak-independent signaling pathway. J Biol Chem. 1996; 271(42):25731-4. DOI: 10.1074/jbc.271.42.25731. View

Herskowitz I, Park H, Sanders S, Valtz N, Peter M . Programming of cell polarity in budding yeast by endogenous and exogenous signals. Cold Spring Harb Symp Quant Biol. 1995; 60:717-27. DOI: 10.1101/sqb.1995.060.01.078. View

Teramoto H, Coso O, Miyata H, Igishi T, Miki T, Gutkind J . Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J Biol Chem. 1996; 271(44):27225-8. DOI: 10.1074/jbc.271.44.27225. View

Wang X, Diener K, Jannuzzi D, Trollinger D, Tan T, Lichenstein H . Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem. 1996; 271(49):31607-11. DOI: 10.1074/jbc.271.49.31607. View

Ichijo H, Nishida E, Irie K, Ten Dijke P, Saitoh M, Moriguchi T . Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997; 275(5296):90-4. DOI: 10.1126/science.275.5296.90. View

Peter M, Neiman A, Park H, van Lohuizen M, Herskowitz I . Functional analysis of the interaction between the small GTP binding protein Cdc42 and the Ste20 protein kinase in yeast. EMBO J. 1996; 15(24):7046-59. PMC: 452530. View

10.

Leberer E, Wu C, Leeuw T, Fourest-Lieuvin A, Segall J, Thomas D . Functional characterization of the Cdc42p binding domain of yeast Ste20p protein kinase. EMBO J. 1997; 16(1):83-97. PMC: 1169616. DOI: 10.1093/emboj/16.1.83. View

11.

Fanger G, Gerwins P, Widmann C, Jarpe M, Johnson G . MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases?. Curr Opin Genet Dev. 1997; 7(1):67-74. DOI: 10.1016/s0959-437x(97)80111-6. View

12.

Westwick J, Lambert Q, Clark G, Symons M, Van Aelst L, Pestell R . Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol Cell Biol. 1997; 17(3):1324-35. PMC: 231857. DOI: 10.1128/MCB.17.3.1324. View

13.

Orci L, Tagaya M, Amherdt M, Perrelet A, Donaldson J, Lippincott-Schwartz J . Brefeldin A, a drug that blocks secretion, prevents the assembly of non-clathrin-coated buds on Golgi cisternae. Cell. 1991; 64(6):1183-95. DOI: 10.1016/0092-8674(91)90273-2. View

14.

Kyriakis J, App H, Zhang X, Banerjee P, Brautigan D, Rapp U . Raf-1 activates MAP kinase-kinase. Nature. 1992; 358(6385):417-21. DOI: 10.1038/358417a0. View

15.

Dent P, Haser W, Haystead T, Vincent L, Roberts T, Sturgill T . Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science. 1992; 257(5075):1404-7. DOI: 10.1126/science.1326789. View

16.

Adamson P, PATERSON H, Hall A . Intracellular localization of the P21rho proteins. J Cell Biol. 1992; 119(3):617-27. PMC: 2289677. DOI: 10.1083/jcb.119.3.617. View

17.

Zhang X, Settleman J, Kyriakis J, Elledge S, Marshall M, Bruder J . Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993; 364(6435):308-13. DOI: 10.1038/364308a0. View

18.

Noel J, Hamm H, SIGLER P . The 2.2 A crystal structure of transducin-alpha complexed with GTP gamma S. Nature. 1993; 366(6456):654-63. DOI: 10.1038/366654a0. View

19.

Manser E, Leung T, Salihuddin H, Zhao Z, Lim L . A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994; 367(6458):40-6. DOI: 10.1038/367040a0. View

20.

Ladinsky M, Kremer J, Furcinitti P, McIntosh J, Howell K . HVEM tomography of the trans-Golgi network: structural insights and identification of a lace-like vesicle coat. J Cell Biol. 1994; 127(1):29-38. PMC: 2120188. DOI: 10.1083/jcb.127.1.29. View