MAP4K3/GLK: Structure, molecular pharmacology and drug development

The serine/threonine kinase MAP4K3 (mitogen activated protein kinase kinase kinase kinase 3, also known as GLK, germinal-center kinase-like kinase) is a member of MAP4Ks, belonging to the mammalian Ste20-like kinase family. MAP4Ks act as upstream regulators in the mitogen-activated protein kinase (MAPK) signaling cascade, activating downstream kinases such as MAPK kinase kinases (MAP3Ks), which in turn activate MAPK kinases (MAP2Ks), and ultimately MAPKs [1]. This cascade is crucial for the transduction of extracellular signals into cellular responses. Three members of MAPKs, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK), commonly form multi-tiered pathways to modulate complex biological processes, including gene expression, cell differentiation, proliferation, and death [2,3]. Up to now, six MAP4K family members have been discovered, which are hematopoietic progenitor kinase 1 (MAP4K1/HPK1), germinal center kinase (MAP4K2/GCK/RAB8IP), GCK-like kinase (MAP4K3/GLK), HPK1/GCK-like kinase (MAP4K4/HGK), kinase homologous to SPS1/Ste20 (MAP4K5/KHS), and misshapen/Nck-related kinase (MAP4K6/MINK), respectively [1]. These kinases have been reported to be involved in a myriad of biological functions, including cell growth, stress response, and immunological regulation. Due to the functional redundancy and negative regulatory effects conducted by each individual MAP4K family member, it is extremely challenging to develop efficient therapeutics to modulate cellular signaling pathways mediated by MAP4Ks. GLK strengthens T-cell effector functions, whereas HPK1 functions as a negative regulator of TCR-mediated activation. The opposing functions of these kinases maintain immune homeostasis, and their dysregulation has been pathogenically linked to diverse immune-related pathologies, including autoimmunity, immunodeficiency syndromes, and tumor immune evasion, highlighting their promise as complementary therapeutic targets for immune modulation. Recently, the encouraging clinical data of HPK1 inhibitors alone or in combination with anti-PD-1 monoclonal antibody for tumor immunotherapy (NCT05878691, NCT04649385) have inspired particular attention to the development of individual MAP4K member-specific inhibitors. Furthermore, GLK's critical role in potentiating TCR activation signaling positions it as a promising therapeutic target for autoimmune pathologies, particularly in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and adult-onset Still's disease (AOSD), where aberrant T-cell activation drives disease progression.In 1997, GLK was first identified by Diener et al. from screening a human skeletal muscle cDNA library by using degenerate oligonucleotide PCR primers. The kinase domain of human GLK (MAP4K3) exhibits 66 % amino acid sequence identity to HPK1 (MAP4K1) and 72 % identity to GCK (MAP4K2) [4]. Thus, it was classified as a MAP4K family member and named MAP4K3. GLK has six alternative splicing forms, among which five missense variants have been reported, but their significance remains undetermined. It is mainly expressed in the human placenta, testis, frontal cortex, pancreas, heart, brain, skeletal muscle, and kidney. Top transcription factor binding sites obtained by QIAGEN in the MAP4K3 gene promoter are AML1a, CUTL1, HSF2, HTF, Msx-1, NF-AT1, PPAR-alpha, RORalpha1, SRF, and SRF (504 AA) (https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAP4K3). It was reported that GLK specifically activated the JNK, but not the ERK1/2 or p38 MAP4K signaling pathways. Both kinase activity and the C-terminal region of GLK are required for maximal activation of JNK [4]. In the past two decades, GLK has been repeatedly reported to regulate multiple signaling pathways and proposed to be a druggable target for developing effective therapeutics in different scenarios.

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