MAP2K2

Official Full Name

mitogen-activated protein kinase kinase 2

Organism

Homo sapiens

GeneID

5605

Background

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

Synonyms

CFC4; MEK2; MKK2; MAPKK2; PRKMK2;

Bio Chemical Class

mRNA target

Protein Sequence

MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQKAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRGLAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQGTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRPPGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADLKMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV

Open

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

1 +

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Detailed Information

MAP2K2 (Mitogen-Activated Protein Kinase Kinase 2) is located on chromosome 19p13.3 and encodes a dual-specificity kinase that belongs to the MAP kinase kinase (MAP2K) family. The gene comprises 11 exons, and its protein product consists of 400 amino acids with a molecular weight of approximately 44 kDa. Structurally, the MAP2K2 protein includes an N-terminal negative regulatory domain, a central kinase domain, and a C-terminal nuclear export signal. The catalytic core lies in the kinase domain, featuring a "catalytic loop" composed of an HRD amino acid motif and an "activation loop" containing phosphorylation sites at Ser222 and Ser226.

As a pivotal component of the MAPK/ERK signaling pathway, MAP2K2 is activated via phosphorylation by upstream MAP3Ks such as RAF kinases. Upon activation, MAP2K2 phosphorylates ERK1 and ERK2 (MAPK1/MAPK3) at the Thr-Glu-Tyr (TEY) motif, propagating downstream signals. Notably, MAP2K2 shares high functional redundancy with its paralog MAP2K1, with approximately 80% sequence homology. Both kinases are capable of phosphorylating ERK1/2, and this redundancy partly explains the lower embryonic lethality in MAP2K2 knockout mice compared to MAP2K1 knockouts, suggesting that they may exert compensatory functions in certain tissues or pathological states.

Figure 1. Central role of MAP2K kinases in the MAPK/ERK pathway. (Andrianova EP, et al., 2023)

Biological Functions and Signal Transduction Mechanisms

MAP2K2 serves as a critical intermediary in cellular signal transduction. When growth factors (e.g., EGF, PDGF) or cytokines bind their respective receptors, RAF kinases (MAP3Ks) are activated through RAS and subsequently phosphorylate MAP2K2 at Ser222/Ser226. Activated MAP2K2 then phosphorylates ERK1/2 at the TEY motif, inducing conformational changes and promoting their nuclear translocation. Inside the nucleus, ERK1/2 phosphorylates transcription factors such as Elk1, c-Fos, and c-Myc, thereby regulating genes involved in cell proliferation, differentiation, and survival.

Importantly, MAP2K2's interaction with scaffold proteins KSR1/2 plays a central role in its regulation. In a resting state, KSR maintains an autoinhibitory conformation that binds MAP2K2. Upon RAS activation, KSR undergoes a conformational shift, releasing MAP2K2 and facilitating its dimerization with BRAF, thus enhancing RAF signal transduction.

Innovative Applications in Immunoregulation and Organ Transplantation

Professor Kexiang Liu's team at Jilin University has pioneered research into the role of circular RNA derived from MAP2K2 (circMAP2K2) in inducing immune tolerance via dendritic cells (DCs) following organ transplantation. circMAP2K2 is generated through back-splicing of exons 3 to 7 of the MAP2K2 gene, with expression levels increasing during DC maturation. Knockdown of circMAP2K2 via siRNA drives DCs toward a tolerogenic phenotype (Tol-DCs), characterized by downregulated expression of surface maturation markers (MHCII, CD40, CD80), reduced secretion of proinflammatory cytokines (IL-6, TNF-α), and enhanced induction of regulatory T cells (Tregs).

Mechanistically, circMAP2K2 interacts with SENP3 (SUMO-specific protease 3), maintaining activation of the NF-κB pathway. Knockdown of circMAP2K2 leads to decreased SENP3 expression, resulting in suppressed phosphorylation and nuclear translocation of the p65 subunit, thereby blocking NF-κB-mediated inflammatory responses. In animal models, infusion of DCs with circMAP2K2 knockdown significantly extended the survival of allogeneic heart grafts in mice (with median survival tripled), accompanied by reduced inflammatory infiltration and fibrosis. Importantly, this immunosuppression is antigen-specific—recipient T cells exhibited tolerance to donor antigens while retaining responsiveness to other antigens, thereby reducing the risks associated with systemic immunosuppression.

Table: MAP2K2-Related Signaling Pathways and Disease Associations

Pathway/Process	Upstream Activators	Downstream Effectors	Associated Diseases
Classical ERK Pathway	RAF kinases, growth factor receptors	ERK1/2, c-Fos, c-Myc	Cancer, Cardio-Facio-Cutaneous (CFC) Syndrome
Chromatin Remodeling	Reprogramming factors	Gatad2b phosphorylation, H3K27 acetylation	Cell reprogramming disorders
Immune Tolerance Induction	circMAP2K2 knockdown	SENP3-p65-NF-κB axis	Organ transplant rejection
Scaffold Protein Interaction	KSR1/2, RAS	BRAF dimerization	Drug resistance

Clinical Relevance and Targeted Therapeutic Strategies

Aberrant activation or loss of MAP2K2 function is closely associated with several developmental disorders and malignancies:

Cardio-Facio-Cutaneous Syndrome Type 4 (CFC4): Gain-of-function mutations in MAP2K2 (e.g., F57S, Q60P) result in Noonan-like phenotypes, including congenital heart defects (e.g., pulmonary stenosis, hypertrophic cardiomyopathy), characteristic craniofacial features (e.g., prominent forehead, hypertelorism), and neurocognitive impairments. These mutations typically occur in the negative regulatory domain, abolishing autoinhibition and causing sustained ERK activation. Unlike mutations in RAS or RAF, MAP2K2 mutations often lead to more pronounced skin manifestations, such as curly hair and hyperkeratosis.
Tumorigenesis and Drug Resistance: In melanoma, colorectal cancer, and lung cancer, MAP2K2 copy number amplification or upstream activators (e.g., BRAF V600E mutation) drive excessive ERK signaling. Notably, treatment with RAF/MEK inhibitors can trigger compensatory activation of MAP2K2, leading to resistance. Second-generation MEK inhibitors (e.g., Trametinib, Cobimetinib) bind allosterically to stabilize the autoinhibited conformation of MAP2K2 and have shown clinical efficacy in BRAF-mutant melanomas.
Pathogen Infections: Bacterial toxins such as YopJ from Yersinia and lethal factor (LF) from Bacillus anthracis suppress host immune responses by inhibiting or degrading MAP2K2, underscoring its essential role in antibacterial defense.

Therapeutic Strategies

Allosteric MEK Inhibitors: These stabilize the autoinhibited kinase conformation via binding to a side pocket in the kinase domain. However, they are associated with side effects such as acneiform rash and retinal vein occlusion.
Dual RAF/MEK Inhibitors: Agents like RO5126766 help overcome compensatory activation seen with monotherapies and enhance antitumor efficacy.
circMAP2K2-Targeted Therapies: In the context of organ transplantation, ex vivo generation of Tol-DCs via siRNA transfection targeting circMAP2K2 offers a promising approach to induce donor-specific immune tolerance, potentially reducing or eliminating the need for systemic immunosuppressants.

As a central hub in the ERK signaling cascade, MAP2K2 remains a clinically validated target. Nevertheless, challenges such as compensatory signaling and toxicity remain. Future research directions include the development of tissue-specific delivery systems, exploration of kinase-independent scaffold functions, and the combination with epigenetic modulators (e.g., histone acetyltransferase inhibitors) to enhance therapeutic outcomes.

References:

Takenouchi T, Shimizu A, Torii C, et al. Multiple café au lait spots in familial patients with MAP2K2 mutation. Am J Med Genet A. 2014 Feb;164A(2):392-6.
Scorrano G, David E, Calì E, Chimenz R, et al. The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications. Genes (Basel). 2023 Nov 22;14(12):2111.
Xu J , Xiong H , Zhao Z , et al . Genistein suppresses allergic contact dermatitis through regulating the MAP2K2/ERK pathway. Food Funct. 2021 May 21;12(10):4556-4569.
Tzivion G. Special issue on mitogen-activated protein kinases: New insights into regulation, function and role in human disease. Biochim Biophys Acta. 2007 Aug;1773(8):1149.
Andrianova EP, Marmion RA, Shvartsman SY, et al. Evolutionary history of MEK1 illuminates the nature of deleterious mutations. PNAS. 2023 Aug 22;120(34):e2304184120.

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