Distantly Related Cousins of MAP Kinase: Biochemical Properties and Possible Physiological Functions

doi:10.1006/bbrc.1999.1705

Biochemical and Biophysical Research Communications

Volume 266, Issue 2, 20 December 1999, Pages 291-295

https://doi.org/10.1006/bbrc.1999.1705 Get rights and content

Abstract

MAP kinases have been established to be key regulators of cellular signal transduction systems and are conserved from baker's yeast to human beings. Until now, three major types of mammalian MAP kinases (ERK, p38, and JNK/SAPK) have been reported and extensively studied. Advancement of genomic research as well as homology cloning techniques has revealed that there are several other protein kinase families that are structurally modestly related to those conventional MAP kinases. Indeed, most of them possess the TXY motif characteristic to MAP kinases in their activation loop, and can be regarded as members of the MAP kinase superfamily, yet some of them show closest overall similarity to Cdks. These kinases, all of mammalian origin, include MAK, MRK, MOK, p42KKIALRE, p56KKIAMRE, NLK, DYRK/Mnb, and Prp4. Although most of their physiological roles remain unknown, recent progress starts shedding some light on their functions.

References (45)

M. Karin et al.
Curr. Biol.
(1995)
T. Hunter
Cell
(1995)
E. Nishida et al.
Trends Biochem. Sci.
(1993)
C.J. Marshall
Curr. Opin. Genet. Dev.
(1994)
T.W. Sturgill et al.
Biochim. Biophys. Acta
(1991)
N.G. Ahn et al.
Curr. Opin. Cell. Biol.
(1992)
R.J. Davis
Trends Biochem. Sci.
(1994)
R.P. Fisher
Curr. Opin. Genet. Dev.
(1997)
G. Zhou et al.
J. Biol. Chem.
(1995)
S. Kamakura et al.
J. Biol. Chem.
(1999)

T.R. Coleman et al.

Curr Opin Cell Biol

(1994)

D.J. Lew et al.

Curr. Opin. Cell Biol.

(1996)

J. Millar et al.

Cell

(1992)

F. Tejedor et al.

Cell

(1995)

W. Becker et al.

J. Biol. Chem.

(1998)

H. Kentrup et al.

J. Biol. Chem.

(1996)

N. Shindoh et al.

Biochem. Biophys. Res. Commun.

(1996)

W.J. Song et al.

Genomics

(1996)

T. Misteli et al.

Trends Cell Biol.

(1997)

J.M. Kyriakis et al.

BioEssays

(1996)

J.N. Lavoie et al.

Prog. Cell Cycle Res.

(1996)

M.H. Cobb et al.

J. Biol. Chem.

(1995)

Cited by (130)

Entanglement of MAPK pathways with gene expression and its omnipresence in the etiology for cancer and neurodegenerative disorders
2023, Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Mitogen Activated Protein Kinase (MAPK) is one of the most well characterized cellular signaling pathways that controls fundamental cellular processes including proliferation, differentiation, and apoptosis. These cellular functions are consequences of transcription of regulatory genes that are influenced and regulated by the MAP-Kinase signaling cascade. MAP kinase components such as Receptor Tyrosine Kinases (RTKs) sense external cues or ligands and transmit these signals via multiple protein complexes such as RAS–RAF, MEK, and ERKs and eventually modulate the transcription factors inside the nucleus to induce transcription and other regulatory functions. Aberrant activation, dysregulation of this signaling pathway, and genetic alterations in any of these components results in the developmental disorders, cancer, and neurodegenerative disorders. Over the years, the MAPK pathway has been a prime pharmacological target, to treat complex human disorders that are genetically linked such as cancer, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current review re-visits the mechanism of MAPK pathways in gene expression regulation. Further, a current update on the progress of the mechanistic understanding of MAPK components is discussed from a disease perspective.
The carboxyl-terminal region of SDCCAG8 comprises a functional module essential for cilia formation as well as organ development and homeostasis
2022, Journal of Biological Chemistry
In humans, ciliary dysfunction causes ciliopathies, which present as multiple organ defects, including developmental and sensory abnormalities. Sdccag8 is a centrosomal/basal body protein essential for proper cilia formation. Gene mutations in SDCCAG8 have been found in patients with ciliopathies manifesting a broad spectrum of symptoms, including hypogonadism. Among these mutations, several that are predicted to truncate the SDCCAG8 carboxyl (C) terminus are also associated with such symptoms; however, the underlying mechanisms are poorly understood. In the present study, we identified the Sdccag8 C-terminal region (Sdccag8-C) as a module that interacts with the ciliopathy proteins, Ick/Cilk1 and Mak, which were shown to be essential for the regulation of ciliary protein trafficking and cilia length in mammals in our previous studies. We found that Sdccag8-C is essential for Sdccag8 localization to centrosomes and cilia formation in cultured cells. We then generated a mouse mutant in which Sdccag8-C was truncated (Sdccag8^ΔC/ΔC mice) using a CRISPR-mediated stop codon knock-in strategy. In Sdccag8^ΔC/ΔC mice, we observed abnormalities in cilia formation and ciliopathy-like organ phenotypes, including cleft palate, polydactyly, retinal degeneration, and cystic kidney, which partially overlapped with those previously observed in Ick- and Mak-deficient mice. Furthermore, Sdccag8^ΔC/ΔC mice exhibited a defect in spermatogenesis, which was a previously uncharacterized phenotype of Sdccag8 dysfunction. Together, these results shed light on the molecular and pathological mechanisms underlying ciliopathies observed in patients with SDCCAG8 mutations and may advance our understanding of protein–protein interaction networks involved in cilia development.
Protein quality control of DYRK family protein kinases by the Hsp90-Cdc37 molecular chaperone
2021, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
Five members of the family, namely DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4, share homologous catalytic domains in the middle of their amino acid sequences [4]. The kinase domains of DYRKs are distantly related to those of MAP kinases [5], suggesting that DYRKs may play roles in cellular signal transduction systems. DYRKs possess various N- and C-terminal stretches, therefore, each of DYRKs may interact with different protein partners to be involved in different cellular signaling pathways in cells.
The DYRK (Dual-specificity tYrosine-phosphorylation Regulated protein Kinase) family consists of five related protein kinases (DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4). DYRKs show homology to Drosophila Minibrain, and DYRK1A in human chromosome 21 is responsible for various neuronal disorders including human Down syndrome. Here we report identification of cellular proteins that associate with specific members of DYRKs. Cellular proteins with molecular masses of 90, 70, and 50-kDa associated with DYRK1B and DYRK4. These proteins were identified as molecular chaperones Hsp90, Hsp70, and Cdc37, respectively. Microscopic analysis of GFP-DYRKs showed that DYRK1A and DYRK1B were nuclear, while DYRK2, DYRK3, and DYRK4 were mostly cytoplasmic in COS7 cells. Overexpression of DYRK1B induced nuclear re-localization of these chaperones with DYRK1B. Treatment of cells with specific Hsp90 inhibitors, geldanamycin and 17-AAG, abolished the association of Hsp90 and Cdc37 with DYRK1B and DYRK4, but not of Hsp70. Inhibition of Hsp90 chaperone activity affected intracellular dynamics of DYRK1B and DYRK4. DYRK1B and DYRK4 underwent rapid formation of cytoplasmic punctate dots after the geldanamycin treatment, suggesting that the chaperone function of Hsp90 is required for prevention of protein aggregation of the target kinases. Prolonged inhibition of Hsp90 by geldanamycin, 17-AAG, or ganetespib, decreased cellular levels of DYRK1B and DYRK4. Finally, DYRK1B and DYRK4 were ubiquitinated in cells, and ubiquitinated DYRK1B and DYRK4 further increased by Hsp90 inhibition with geldanamycin. Taken together, these results indicate that Hsp90 and Cdc37 discriminate specific members of the DYRK kinase family and play an important role in quality control of these client kinases in cells.
Enriched expression of the ciliopathy gene Ick in cell proliferating regions of adult mice
2018, Gene Expression Patterns
Cilia are essential for sensory and motile functions across species. In humans, ciliary dysfunction causes “ciliopathies”, which show severe developmental abnormalities in various tissues. Several missense mutations in intestinal cell kinase (ICK) gene lead to endocrine-cerebro-osteodysplasia syndrome or short rib-polydactyly syndrome, lethal recessive developmental ciliopathies. We and others previously reported that Ick-deficient mice exhibit neonatal lethality with developmental defects. Mechanistically, Ick regulates intraflagellar transport and cilia length at ciliary tips. Although Ick plays important roles during mammalian development, roles of Ick at the adult stage are poorly understood. In the current study, we investigated the Ick gene expression in adult mouse tissues. RT-PCR analysis showed that Ick is ubiquitously expressed, with enrichment in the retina, brain, lung, intestine, and reproductive system. In the adult brain, we found that Ick expression is enriched in the walls of the lateral ventricle, in the rostral migratory stream of the olfactory bulb, and in the subgranular zone of the hippocampal dentate gyrus by in situ hybridization analysis. We also observed that Ick staining pattern is similar to pachytene spermatocyte to spermatid markers in the mature testis and to an intestinal stem cell marker in the adult small intestine. These results suggest that Ick is expressed in proliferating regions in the adult mouse brain, testis, and intestine.
Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation
2018, Journal of Molecular Biology
Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia.
Hsp90: Friends, clients and natural foes
2016, Biochimie
Hsp90, a homodimeric ATPase, is responsible for the correct folding of a number of newly synthesized polypeptides in addition to the correct folding of denatured/misfolded client proteins. It requires several co-chaperones and other partner proteins for chaperone activity. Due to the involvement of Hsp90-dependent client proteins in a variety of oncogenic signaling pathways, Hsp90 inhibition has emerged as one of the leading strategies for anticancer chemotherapeutics. Most of Hsp90 inhibitors blocks the N terminal ATP binding pocket and prevents the conformational changes which are essential for the loading of co-chaperones and client proteins. Several other inhibitors have also been reported which disrupt chaperone cycle in ways other than binding to N terminal ATP binding pocket. The Hsp90 inhibition is associated with heat shock response, mediated by HSF-1, to overcome the loss of Hsp90 and sustain cell survival. This review is an attempt to give an over view of all the important players of chaperone cycle.

View all citing articles on Scopus

View full text

Breakthroughs & ViewsDistantly Related Cousins of MAP Kinase: Biochemical Properties and Possible Physiological Functions

Abstract

Curr. Biol.

Cell

Trends Biochem. Sci.

Curr. Opin. Genet. Dev.

Biochim. Biophys. Acta

Curr. Opin. Cell. Biol.

Trends Biochem. Sci.

Curr. Opin. Genet. Dev.

J. Biol. Chem.

J. Biol. Chem.

Curr Opin Cell Biol

Curr. Opin. Cell Biol.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Genomics

Trends Cell Biol.

BioEssays

Prog. Cell Cycle Res.

J. Biol. Chem.

Breakthroughs & Views
Distantly Related Cousins of MAP Kinase: Biochemical Properties and Possible Physiological Functions