MAP4K1

Official Full Name

mitogen-activated protein kinase kinase kinase kinase 1

Organism

Homo sapiens

GeneID

11184

Background

Enables ATP binding activity and MAP kinase kinase kinase kinase activity. Involved in several processes, including JNK cascade; cellular response to phorbol 13-acetate 12-myristate; and protein phosphorylation. Located in membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

HPK1;

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Detailed Information

Mitogenactivated protein kinase kinase 1 (MAP4K1, also known as hematopoietic stem cell kinase 1, HPK1) is a 97 kD protein expressed mainly in hematopoietic organs and cells. It is a mammalian Ste20-associated serine/threonine kinase belonging to the mitogen-activated protein kinase kinase kinase kinase (MAP4K) family. It can be activated by various signal stimuli, including epidermal growth factor (EGF), prostaglandin E2 (PGE2), tumor growth factor beta (TGF-β), and erythropoietin ( Erythropoietin (EPO) and TCR/B cell receptor (BCR).

MAP4K1 Function

MAP4K1 plays various roles in immunity. As a member of the MAP4K family, it can transduce the signal to MAP2K via MAP3K, ultimately leading to the activation of c-Jun N-terminal kinase (JNK). The JNK family is involved in a variety of T cell responses, including Th1/Th2 differentiation, cell proliferation, and apoptosis. Immunohistochemical analysis of paraffin specimens of extramammary paget's disease revealed that MAP4K1 plays an important role in the pathogenesis of extra-emeriatric eczema-like cancer through the JNK pathway.

Figure 1. JNK activation by MAP4K-mediated cascade. (Chuang, et al. 2015)

In addition, activation of NF-κB has been found to protect cells from apoptosis. FasL is also an apoptosis inducer of T cells. MAP4K1 can simultaneously regulate JNK, NF-κB and FasL, which makes it a very complex and even contradictory role in controlling cell proliferation and apoptosis. In addition to regulating cell proliferation and apoptosis, MAP4K1 is also a negative regulator of TCR/BCR signaling and T/B/dendritic cell-mediated immune responses. Due to its important role in immunity, MAP4K1 plays an important role in autoimmune diseases (such as systemic lupus erythematosus, psoriatic arthritis), tumors (such as acute myeloid leukemia, bladder epithelial cancer, Paget's disease of the breast, colon cancer, Lewis lung cancer, pancreatic cancer) and inflammatory responses.

Interaction Between MAP4K1 and Adaptor Proteins

Linker proteins are proteins that do not themselves have kinase or phosphatase activity and transcriptional activity. Once the upstream signal is received, the adaptor protein recruits MAP4K1 from the cytoplasm to the activated receptor located in the cell membrane or glycolipid enriched microdomain (GEM, also known as lipid raft), thereby promoting subsequent MAP4K1 activation and Downstream signal events. Some adaptor proteins also bind the protein tyrosine kinase (PTK) to MAP4K1. As a member of the MAP4K family, it is involved in a variety of adaptor proteins, such as CARD11, HSI, HIP-55, GRB2 family, LAT, SLP-76 family, CRK family, BAM32, etc. It is involved in a variety of immune responses, including regulation of cell proliferation and apoptosis, inhibition of TCR/BCR signaling and T/B/dendritic cell-mediated immune responses, and plays an important role in autoimmune diseases, tumors and inflammatory responses.

The caspase recruitment domain family member 11 (CARD11) belongs to the membrane-associated guanylate kinase (MAGUK) family. The interaction of MAP4K1 with CARD11 is primarily mediated by the coiled-coil region of CARD11 and the caspase recruitment region. Once stimulated by TCR, MAP4K1 phosphorylates the junction of CARD11.

HPK1-interacting protein of 55kD is an upstream activator of the MAP4K1 and JNK1 signaling pathways and synergistically inhibits the transcriptional activity of activated nuclear factor of activated T-cells (NFAT) with MAP4K1. Once stimulated by TCR/BCR, HIP-55 can bind MAP4K1 and recruit it to the contact site of T/B cell-antigen presenting cell (APC), where MAP4K1 interacts with its substrates and down-regulates the TCR/BCR signaling pathway.

References:

Chuang, Wang, Tan, & TH. (2015). Map4k family kinases in immunity and inflammation. Advances in Immunology, 129, 277-314.
Jakob, S. M. , Pick, R. , Brechtefeld, D. , Nussbaum, C. , Kiefer, F. , & Sperandio, M. , et al. (2013). Hematopoietic progenitor kinase 1 (hpk1) is required for lfa-1–mediated neutrophil recruitment during the acute inflammatory response. Blood,121(20), 4184-4194.
Simon, S. I. . (2013). Gimme a brake: hpk1 regulates lfa-1 and neutrophil traction. Blood, 121(20), 4017-4018.

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