Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 as a Putative Effector of Rap2 to Activate the c-Jun N-terminal Kinase

Machida, Noriko; Umikawa, Masato; Takei, Kimiko; Sakima, Nariko; Myagmar, Bat-Erdene; Taira, Kaoru; Uezato, Hiroshi; Ogawa, Yoshihide; Kariya, Ken-ichi

doi:10.1074/jbc.c300542200

Cited by 119 publications

(96 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results suggest that the C-terminal regulatory domain of hMINK␤ plays a dominant role in the regulation of cell morphology in HT1080 cells. Because this portion of hMINK␤ contains two domains that have been shown to be involved in protein-protein interactions (5)(6)(7)(8), the observed effects may be mediated by hMINK␤ interacting with and sequestering the cellular factors essential for its functions. Cell morphology changes are coincident with the alterations of cellmatrix adhesion.…”

Section: Functional Characterization Of a Novel Human Mink Isoform 54393mentioning

confidence: 99%

“…40 h post-transfection, the cells were harvested and lysed in the buffer containing 50 mM Tris-HCl, pH 8.0, 200 mM NaCl, and 1% Nonidet P-40 supplemented with 10 mM ␤-glycerophospate, 5 mM NaF, 1 mM Na 3 VO 4 , 1 mM dithiothreitol, and the protease inhibitor mixture (Calbiochem). Immunoprecipitation and in vitro kinase reaction for Myc-JNK2 were performed as described previously (7). For the hMINK␤ kinase reaction, hMINK␤ proteins were immunoprecipitated with anti-FLAG beads (Sigma) and subjected to an in vitro kinase reaction in the presence of [␥-32p ]ATP and 5 g of myelin basic protein (MBP, Upstate Biotechnology).…”

Section: Cell Lines and Reagents-phoenixmentioning

confidence: 99%

“…In addition, the association with MEKK1 is required to activate the JNK pathway. MAP4K4, a member of GCK-IV subfamily kinases, interacted with small GTP-binding protein Rap2 through its CNH domain (7).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ

Leo

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Misshapen/NIKs-related kinase (MINK) is a member of the germinal center family of kinases that are homologous to the yeast sterile 20 (Ste20) kinases and regulate a wide variety of cellular processes, including cell morphology, cytoskeletal rearrangement, and survival. Here, we present the cloning and functional characterization of a novel human Misshapen/NIKs-related kinase ␤ (hMINK␤) that encodes a polypeptide of 1312 amino acids. hMINK␤ is ubiquitously expressed in most tissues with at least five alternatively spliced isoforms. Similar to Nck interacting kinase (NIK) and Traf2 and Nck-interacting kinase (TNIK), hMINK␤ moderately activates c-Jun N-terminal kinase (JNK) and associates with Nck via the intermediate domain in the yeast two-hybrid system and in a glutathione S-transferase (GST) pulldown assay. Interestingly, overexpression of the kinase domain deleted and kinase-inactive mutants of hMINK␤ in human fibrosarcoma HT1080 cells enhanced cell spreading, actin stress fiber formation, and adhesion to extracellular matrix, as well as decreased cell motility and cell invasion. Furthermore, these mutants also promoted cell-cell adhesion in human breast carcinoma MCF7 cells, evidenced with cell growth in clusters and increased membrane localization of ␤-catenin, a multifunctional protein involved in E-cadherin-mediated cell adhesion. Finally, hMINK␤ protein was found to colocalize with the Golgi apparatus, implicating that hMINK␤ might exert its functions, at least in part, through the modulation of intracellular protein transport. Taken together, these results suggest that hMINK␤ plays an important role in cytoskeleton reorganization, cell adhesion, and cell motility.

show abstract

Section: Functional Characterization Of a Novel Human Mink Isoform 54393mentioning

confidence: 99%

Section: Cell Lines and Reagents-phoenixmentioning

confidence: 99%

See 1 more Smart Citation

Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ

Leo

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…RPIP9 expression is activated during malignant breast epithelial transformation and increases with the progression toward an invasive phenotype (15). Tumor necrosis factor receptor-associated factor 2 (Traf2)-and Nck-interacting kinase (TNIK) is a recently identified Rap2-specific effector that is distinct from RPIP8 (16,17). TNIK interacts with Rap2 through its C-terminal regulatory domain, termed the CNH domain, and regulates the actin cytoskeleton.…”

mentioning

confidence: 99%

Crystal Structure of the RUN Domain of the RAP2-interacting Protein x

Kukimoto-Niino¹,

Takagi²,

Akasaka³

et al. 2006

J. Biol. Chem.

View full text Add to dashboard Cite

Rap2-interacting protein x (RPIPx) is a homolog of RPIP8, a specific effector of Rap2 GTPase. The N-terminal region of RPIP8, which contains the RUN domain, interacts with Rap2. Using cell-free synthesis and NMR, we determined that the region encompassing residues 83-255 of mouse RPIPx, which is 40-residues larger than the predicted RUN domain (residues 113-245), is the minimum fragment that forms a correctly folded protein. This fragment, the RPIPx RUN domain, interacted specifically with Rap2B in vitro in a nucleotide-dependent manner. The crystal structure of the RPIPx RUN domain was determined at 2.0 Å of resolution by the multiwavelength anomalous dispersion (MAD) method. The RPIPx RUN domain comprises eight anti-parallel ␣-helices, which form an extensive hydrophobic core, followed by an extended segment. The residues in the core region are highly conserved, suggesting the conservation of the RUN domain-fold among the RUN domain-containing proteins. The residues forming a positively charged surface are conserved between RPIP8 and its homologs, suggesting that this surface is important for Rap2 binding. In the crystal the putative Rap2 binding site of the RPIPx RUN domain interacts with the extended segment in a segment-swapping manner.The small GTPases of the Ras family function as molecular switches, regulating diverse cellular processes such as proliferation and differentiation (1, 2). They cycle between the GTPbound, activated forms and the GDP-bound, inactivated forms, with the aid of regulatory proteins, such as guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Between the GTP-bound and GDP-bound forms, conformational changes occur in two conserved regions, the switch-I and switch-II regions. The switch-I region encompasses the "effector region," through which the GTP-bound forms interact with their effectors that activate downstream targets.The Ras family consists of Ras (H-, K-, and N-Ras), M-Ras, R-Ras, TC21, Rap1 (Rap1A and B), Rap2 (Rap2A and B), Ral, Rheb, Rin, and Rit (3). Rap1 and Rap2 are very close relatives (ϳ60% sequence identity), and they exhibit ϳ50% sequence identity with Ras (4). Rap1 and Ras share an identical effector region, whereas in Rap2, the single replacement of Ser-39 by Phe is observed. Several experiments have shown that Rap1 functions as an antagonist in Ras-signaling pathways, probably by competing for the Ras effectors (5-8). In contrast, Rap2 did not antagonize Ras-induced transformation (9). Rap2 interacts with Ras effectors, such as Raf, phosphatidylinositol 3-kinase (PI3K), and Ral guanine nucleotide dissociation stimulator (GDS), but it only inhibits the activation of the downstream targets of Raf and PI3K and not RalGDS (10 -12). Furthermore, Rap2 is regulated differently by guanine nucleotide exchange factors and GTPase-activating proteins as compared with Rap1 (10), suggesting that Rap1 and Rap2 have distinct signaling functions.Rap2 interacts with its specific effector, Rap2-interacting protein 8 (RP...

show abstract

“…There are various specific effectors of Rap2, including mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), misshapen/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase-related kinase (MINK), tumor necrosis factor receptor-associated factor 2 and noncatalytic region of tyrosine kinase-interacting kinase (TNIK), protein tyrosine phosphatase-like protein 1-associated RhoGAP 1 (PARG1) and Rap2 interacting protein 9 (RPIP9) (41-43). These Rap2 specific effectors interact with Rap2 through the C-terminal Citron homology domain (44).…”

Section: Potential Downstream Effectors Of Rap2bmentioning

confidence: 99%

Structure, functional regulation and signaling properties of Rap2B

Qu¹,

Huang²,

Di³

et al. 2016

Oncology Letters

View full text Add to dashboard Cite

Abstract. The Ras family small guanosine 5'-triphosphate (GTP)-binding protein Rap2B is is a member of the Ras oncogene family and a novel target of p53 that regulates the p53-mediated pro-survival function of cells. The Rap2B protein shares ~90% homology with Rap2A, and its sequence is 70% identical to other members of the Rap family such as RaplA and RaplB. As a result, Rap2B has been theorized to have similar signaling effectors to the GTPase-binding protein Rap, which mediates various biological functions, including the regulation of sterile 20/mitogen-activated proteins. Since its identification in the early 1990s, Rap2B has elicited a considerable interest. Numerous studies indicate that Rap2B exerts specific biological functions, including binding and stimulating phospholipase C-ε and interferon-γ. In addition, downregulation of Rap2B affects the growth of melanoma cells. The present review summarizes the possible effectors and biological functions of Rap2B. Increasing evidence clearly supports the association between Rap2B function and tumor development. Therefore, it is conceivable that anticancer drugs targeting Rap2B may be generated as novel therapies against cancer.

show abstract

Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 as a Putative Effector of Rap2 to Activate the c-Jun N-terminal Kinase

Cited by 119 publications

References 14 publications

Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ

Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ

Crystal Structure of the RUN Domain of the RAP2-interacting Protein x

Structure, functional regulation and signaling properties of Rap2B

Contact Info

Product

Resources

About