MAP4K4: an emerging therapeutic target in cancer

Abstract

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.

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas

“…GISTIC analysis identified significantly recurrent deletions of CDKN2A (deleted in 61% of samples, with 45% of deletions biallelic) and ARID1A (deleted in 28% of samples). Significantly recurrent amplifications included TNFRSF1B (amplified in 33%), which encodes the NF-kB pathway activating oncogene TNFR2 40 , and MAP4K4 (amplified in 17%), an activator of ERK signaling associated with poor outcomes in numerous cancers 41 . In addition, we found focal deletions common in other T cell cancers 42,43 (FAS and PDCD1) in 22% of cases each, one sample each with biallelic deletion of FAS or PDCD1.…”

STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation

“…MAP4K4 is less well characterized than other members of the MAPK family but has been implicated in a number of biological processes including invasion, insulin resistance and immunity (Collins et al 2006, Tang et al 2006, Huang et al 2014, Danai et al 2015, Vitorino et al 2015. Indeed, MAP4K4 has been reported to promote invasion and to act as a downstream component of TNF-α signaling (Wright et al 2003, Crawford et al 2014, Gao et al 2016. However, others have found evidence that MAP4K4 can also act as a candidate tumor suppressor gene (Westbrook et al 2005), promote apoptosis downstream of Sox2 , Yang et al 2015 and serve as a regulator of the Hippo pathway, in part through direct phosphorylation of LATS1/2, leading to YAP/TAZ inhibition (Couzens et al 2013, Mohseni et al 2014, Meng et al 2015, Zheng et al 2015.…”

Pancreatic Ductal Adenocarcinoma: MicroRNAs Affecting Tumor Growth and Metastasis in Preclinical In Vivo Models

“…Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) has been identified as a direct target of miR-141 (46) (Figure 3). MAP4K4, a serine-threonine kinase, is involved in migration, proliferation and regulation of focal adhesion dynamics (47,48). Expression levels of MAP4K4 are associated with worse prognosis in patients with stage II PDAC (49).…”