MAP4K4: an emerging therapeutic target in cancer
© The Author(s) 2016
Received: 2 September 2016
Accepted: 4 October 2016
Published: 28 October 2016
The serine/threonine kinase MAP4K4 is a member of the Ste20p (sterile 20 protein) family. MAP4K4 was initially discovered in 1995 as a key kinase in the mating pathway in Saccharomyces cerevisiae and was later found to be involved in many aspects of cell functions and many biological and pathological processes. The role of MAP4K4 in immunity, inflammation, metabolic and cardiovascular disease has been recognized. Information regarding MAP4K4 in cancers is extremely limited, but increasing evidence suggests that MAP4K4 also plays an important role in cancer and MAP4K4 may represent a novel actionable cancer therapeutic target. This review summarizes our current understanding of MAP4K4 regulation and MAP4K4 in cancer. MAP4K4-specific inhibitors have been recently developed. We hope that this review article would advocate more basic and preclinical research on MAP4K4 in cancer, which could ultimately provide biological and mechanistic justifications for preclinical and clinical test of MAP4K4 inhibitor in cancer patients.
KeywordsMAP4K4 Cancer Therapeutic target Signaling pathways
MAP4K4, also known as HGK (hematopoietic progenitor kinase/germinal center kinase-like kinase) or NIK (Nck interacting kinase, the mouse ortholog) is a serine/threonine (S/T) kinase that belongs to the mammalian family of Ste20 protein kinases due to their shared homology to the budding yeast kinase Ste20p . Ste20 family consists of more than 30 members that can be divided into two subgroups based on the location of their catalytic domains (N-terminals vs. C-terminals): the p21-activated kinases (PAKs, C-terminals) and the germinal center-like kinases (GCKs, N-terminals) . Based on the wide variety of structure in the noncatalytic regions of the GCKS, these kinases are further divided into eight subfamilies . MAP4K4 is one of four members of the mammalian GCK-IV subfamily [1, 3–6].
MAP4K4 contains ~1200 amino acids with a molecular mass of ~140 KDa [7, 8]. The orthologues of MAP4K4 among different species share similar molecular structure. Human MAP4K4 gene is located at 2q11.2 in human chrome . MAP4K4 is expressed in all tissue types examined  but appears to express at relatively higher levels in the brain and testis . Five alternatively spliced transcript variants encoding different isoforms of human MAP4K4 can be found in NCBI database. These splice variants contain identical kinase domain at the N-terminus and alternative splicing appears to mainly affect the intermediate regions of MAP4K4. Mouse MAP4K4 (NIK) has two proline-rich motifs in its intermediate domain through which NIK binds with SH3 (the SRC homology 3) domain of NCK adapter protein [8, 10]. The long version of MAP4K4 and MAP4K4 cloned from tumor cells, but not the short version of MAP4K4, also contain proline-rich regions . Although the biological significance of all MAP4K4 isoforms remains to be determined, it is reasonable to speculate that variation in the middle domain could affect MAP4K4 interaction with other factors, resulting in different biochemical and physiological consequences. While multiple isoforms can be present in the same cell, the relative abundance of each isoform in a given cell appears to be different in a cell-type or tissue-type specific manner . For instance, the shorter version of MAP4K4 is predominately expressed in human brain, liver, skeletal muscle and placenta, the longer version is more abundant in the brain . The tissue-specific expression patterns of MAP4K4 isoforms could suggest that each isoform may have a distinct or tissue-specific function or the regulation of each isoform could be tissue- or cell type-specific.
Summary of MAP4K4 knockout mouse models
Reduced plasma glucose levels and enhanced insulin sensitivity
Skin conditional knockout
Aberrant wound repair and epidermal cell migration defects
T cell-specific knockout
Systemic inflammation and type 2 diabetes
Endothelial cell-specific knockout
Endothelial cell-specific inducible knockout
Protected from vascular inflammation and atherosclerosis
Regulation of MAP4K4 kinase activity and gene expression
Taking the global phosphoproteomics approach and by comparing the corresponding SILAC (Stable Isotope Labeling by Amino acids in Cell) ratios of EGF (epidermal growth factor) stimulation and erlotinib (EGFR inhibitor) treatment in lung adenocarcinoma cells, a prior study identified two serine sites S648 and S708 in the middle domain of MAP4K4 as EGFR (epidermal growth factor receptor) signaling-dependent phosphorylation sites . Serine 648 is conserved among the five MAP4K4 isoforms mentioned above [7, 9], but serine 708 is missing in the corresponding position of the above isoforms, suggesting that there could be an unidentified isoform of MAP4K4 or it was simply due to incorrect matches . Although phosphorylation of these sites need to be further verified by mutation strategy and the biochemical and biological consequences of these phosphorylations remain to be determined, the observation that in vivo phosphorylation of these sites are regulated by EGFR signaling strongly support that the intermediate regions of MAP4K4 may also play an important role in the regulation of MAP4K4 activity or function.
The C-terminal domain of MAP4K4 contains a citron-homology domain (CNH) that appears to determine MAP4K4 association with other factors . For instance, MAP4K4 interaction with Rap2 requires the entire CNH domain . A human guanylate-binding protein (GBP) hGBP3, binds to the C-terminal regulatory domain of MAP4K4 . Presumably through affecting protein–protein interaction, the C-terminal domain of MAP4K4 is believed to be involved in the regulation of MAP4K4 activity. It has been shown that full activation of SAPK (Stress-activated protein kinases, also known as Jun amino-terminal kinases, JNK) by MAP4K4 requires both MAP4K4′s kinase activity and the C-terminal regulatory domain that mediates the association of MAP4K4 with MEKK1 (mitogen-activated protein kinase kinase kinase 1) . Although protein–protein interaction appears to determine MAP4K4 kinase activity, MAP4K4 interaction with other proteins appears to not require its kinase activity. The results of coimmunoprecipitation assay have shown that wild-type MAP4K4 and kinase-inactive MAP4K4 (MAP4K4-K54R) exerted similar binding affinity to transcription factor STAT3 (signal transducer and activator of transcription 3) in human embryonic kidney (HEK) 293T cells . Consistent with this, MAP4K4 interacts with PYK2 (proline-rich tyrosine kinase 2) through the C-terminal portion of MAP4K4 and the association does not require catalytic activity of MAP4K4 .
Taken together, current evidence, as summarized above, strongly supports that the MAP4K4 kinase activity can be positively or negatively regulated by upstream kinases. The identities of the kinases remain largely unexplored. If multiple kinases are involved, it is highly likely that the selection within a repertoire of candidate kinases is context-dependent, depending on the cell type, the nature of the external stimuli, and the cell state. The biochemical and biological consequences of phosphorylation could also be context-dependent. In addition to negatively or positively regulating MAP4K4 kinase activity, phosphorylation may also determine MAP4K4 subcellular localization and substrate-selection.
A recent study points to a possibility that in T cells of type 2 diabetes patients, mRNA level of MAP4K4 might be affected by enhanced methylation of CpG islands in its promoter region , suggesting epigenetic regulation could play a role in the regulation of MAP4K4 expression. Information regarding regulation of MAP4K4 by natural stimuli and transcription factors is extremely limited. To date, only two factors have been reported to be involved in modulating MAP4K4 expression: TNF-α and p53. TNF-α treatment, through TNF-α receptor 1 (TNFR1), increases MAP4K4 mRNA and protein expression in cultured adipocytes . TNF-α can stimulate MAP4K4 kinase activity in 293T cells  and in rat primary beta cells , which appears not to involve changes in MAP4K4 expression, suggesting mechanisms underlying TNF-α regulation of MAP4K4 is context-dependent. MAP4K4 gene contains a nearby p53 binding sites cluster downstream of the promoter and six potential p53 binding sites in the first intron, four of which are confirmed by chromatin immunoprecipitation (ChIP) experiments [9, 29]. Induction of p53 in p53-Saos-2 cells upregulates MAP4K4 mRNA expression . The physiological relevance of TNF-α- and p53-mediated regulation of MAP4K4 expression still needs to be verified in biological systems, given the fact that both TNF-α and p53 are broadly involved in human biology and diseases, these findings strongly support the notion that modulation of MAP4K4 expression could be an important mechanism of MAP4K4 regulation and could have important biological and clinical significance.
MAP4K4 in cancer
Current information on MAP4K4 in cancer
Tumor type/cell line studied
Patient prognosis correlation
Manipulation of MAP4K4
Year of publication
Suggested downstream effector
Tumors of the digestive system
Colorectal cancer tissues and cell line
MAP4K4 expression was reversely correlated with overall survival and lymph node metastasis
Colorectal cancer tissues and cell line
Cell proliferation↓, colony formation↓, G0/G1 arrest and apoptosis↑
Gastric cancer cells
cell proliferation↓, G1 phase arrest, apoptosis↑ and invasion↓
Notch2, Notch3, Hes1
MAP4K4 expression was a negative predictor of overall survival and early recurrence rate
S phase arrest, apoptosis↑
MAPK/JNK, NF-κB, TLRs
Hepatocellular carcinoma cell line
MMP-2, MMP-9, NF-κB
Pancreatic cancer tissues and cell lines
Cell proliferation↓, colony formation↓, invasion↓, G1 arrest, apoptosis↓, chemosensitivity↑ and xenograft tumor growth↓
Stage II pancreatic ductal adenocarcinoma
MAP4K4 expression was associated with poor overall and recurrence-free survival
Head and neck cancer
Larynx carcinoma cell line
Cell migration↓ and invasion↓
MAP4K4 expression was associated with shorter overall and recurrence-free survival
Lung adenocarcinoma cell lines
Ovarian carcinoma cell line
MAP4K4 was associated with time to biochemical failure
Tumor of the central nervous system
Glioblastoma cell line
Cell migration↓ and invasion↓
Reactivation of Kaposi’s sarcoma herpesvirus and cell invasion↓
COX-2, MMP-7, MMP-13
60 cell lines from NCI tumor panel
Anchorage-independent growth↓, cell invasion↓, cell adhesion↑ and spreading rates↑
In addition to above mentioned candidate downstream mediators of MAP4K4, MAP4K4 also participated in the regulation of other cancer-related signaling pathways or factors including insulin pathway, hippo signaling (LATS1/2 and YAP/TAZ) and mTOR/AMPK [19, 21, 43, 47–52]. Although experimental evidence that supports the link between MAP4K4 and these pathways and cancer is currently not available, it is reasonable to believe that MAP4K4 could contribute to cancer through modulating these pathways or factors in a context-dependent manner.
How MAP4K4 regulates its downstream effectors or signaling mediators remains largely unexplored. Since MAP4K4 is a kinase, one would expect that the primary job of MAP4K4 is to phosphorylate its substrate. Indeed, MAP4K4 can directly phosphorylate TRAF2 at serine 35 to promote its degradation in T cells . However, none of these factors have been proved to be a direct phosphorylation substrate of MAP4K4 in cancer, implying that MAP4K4 regulates these factors or pathways indirectly. Identification of direct substrates of MAP4K4 will provide crucial clues as to how MAP4K4 is mechanistically involved in cancer.
MAP4K4-specific small-molecule inhibitors
Current evidence supports but not yet provides sufficient biological and mechanistic justification for MAP4K4 as a novel cancer therapeutic target. Evidence definitely linking MAP4K4 to the development and progression of any types of cancer is still lacking. To this end, it is essential to examine the impact of genetic manipulation of MAP4K4 in mouse models of cancer. When interpreting results from experiments using MAP4K4 knockout mice (whole-body or tissue-specific knockout), potential redundancy and functional compensation among MAP4Ks should be taken into consideration. Since small-molecule inhibitors of MAP4K4 are available, in order to eventually use these inhibitors in clinic, future studies should attempt to test their tumor prevention and antitumor activity in mouse models of cancer.
Currently there is no sufficient information suggesting in which type of cancer MAP4K4 inhibitor can be used as a novel promising therapy. Target overexpression is an overrated predictor of efficacy since it may also represent a cellular attempt to limit unbridled growth, unless functional results from genetic manipulation of MAP4K4 in that particular tumor model are available, it is difficult to predict cancer types responsive to MAP4K4 inhibitor treatment. It is possible that MAP4K4 could promote tumor development and progression in certain types of cancer and functions as a tumor repressor in other types of cancer, or plays different roles at different stages during tumor development and progression. Therefore it is crucial to gain a thorough understanding of how MAP4K4 is involved in a particular type of cancer functionally and mechanistically before conducting clinical testing of MAP4K4 inhibitor in cancer patients.
No information is available about whether and how MAP4K4 is involved in resistance to standard cancer therapy. If MAP4K4 contributes to cancer development and progression, it is highly likely that MAP4K4 can also be involved in treatment resistance. Therefore in addition to examine the potential anti-tumor activity of MAP4K4 inhibitors as a standalone therapy, it is also important to test if MAP4K4 inhibitors can be used in combination to overcome resistance to chemotherapy, radiation therapy, targeted therapy and immunotherapy.
Detailed molecular understanding of how MAP4K4 is involved in cancer biology is essential for firmly establishing MAP4K4 as a target for that particular type of cancer. Crucial to this effort is to identify key upstream regulators and downstream effectors including substrates of MAP4K4. To develop efficient methods to block MAP4K4, it is also crucial to understand how MAP4K4 functionally interacts with Ste20 family members.
Cancer remains a largely incurable disease, indicating an urgent and unmet need for novel effective therapeutic approaches. Identifying a novel cancer therapeutic target that could be amenable to pharmacologic intervention is challenging. To this end, we believe that a better understanding of biological functions and underlying mechanisms of MAP4K4 in cancer could have far-reaching implications for new directions in cancer therapy.
epidermal growth factor
hematopoietic progenitor kinase/germinal center kinase-like kinase
Jun amino-terminal kinases
mitogen-activated protein kinase kinase kinase kinase 4
Nck interacting kinase
proline-rich tyrosine kinase 2
short hairpin RNA
signal transducer and activator of transcription 3
XG, CG, GL and JH wrote the review. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This work was supported by USPHS Grants CA166197 and CA175202 awarded to Jing Hu; the National Natural Science Foundation of China (Grant Number 81472697) to Guoxiang Liu; and China Scholarship Council, State Scholarship Fund (File Number 201403170260) to Xuan Gao.
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