Table 2.
Summary of interactors and substrates of MAP4K4.
| Interactor | Function | References |
|---|---|---|
| ARP2 | NIK (murine MAP4K4) binds and directly phosphorylates the ARP2 subunit, which enables and increases the nucleating activity of the ARP2/3 complex. | (59) |
| EB2 | MAP4K4 regulates focal adhesion turnover and cell motility by binding to EB2, a microtubule-binding protein, and by binding to IQSEC1, a guanine nucleotide exchange factor to enhance focal adhesion turnover. | (61) |
| Ezrin | MAP4K4/NIK phosphorylates ezrin on the C-terminal regulatory Thr residue and promotes cell motility and invasiveness. | (32, 60) |
| FARP1 | MAP4K4 binds and phosphorylates FARP1. FARP1 contributes to neurite formation and is necessary for dendrite branching. | (77) |
| IQSEC1 | MAP4K4 regulates focal adhesion turnover and cell motility by binding to EB2, a microtubule end binding protein, and by binding to IQSEC1, a guanine nucleotide exchange factor to enhance focal adhesion turnover. | (61) |
| LATS1/2 | MAP4K4 phosphorylates LATS1/2, resulting in YAP/TAZ phosphorylation, cytoplasmatic retention and proteasomal degradation. This function constitutes a core mechanism of Hippo tumor suppressor pathway activation. | (3) |
| MLK3 | MAP4K4 and MLK3 interact and MAP4K4 phosphorylates MLK3 on Thr738, which increases MLK3 kinase activity and downstream signaling. Phosphorylation of MLK3 by MAP4K4 promotes pancreatic cancer cell proliferation, migration, and colony formation. | (78) |
| PYK2 | MAP4K4 as a binding partner of PYK2, which phosphorylates MAP4K4 on Tyr residues. The cooperation of MAP4K4 and PYK2 promotes glioma cell migration. | (79) |
| PKCθ | The cooperation of MAP4K4 and STRN3 in the STRIPAK complex promotes a pro-migratory and invasive phenotype in medulloblastoma cells through the activation of downstream effector PKCθ. | (62) |
| PP2A | MAP4K4 interacts with PP2A in the STRIPAK complex to control cytoskeleton dynamics in cardiomyocytes and Hippo pathway activation in various cell types. | (62, 66, 80) |
| RAP2 | RAP2 GTPase is activated by low extracellular matrix stiffness. Activated RAP2 binds to MAP4K4/6/7, resulting in Hippo pathway activation and MAP4K4/6/7-dependent ubiquitin phosphorylation. | (73, 74) |
| Radixin | MAP4K4 phosphorylates radixin and promotes cell motility and invasiveness. | (60) |
| STRN3 STRN4 |
MAP4K4 binds STRN4, a component of the STRIPAK complex. STRIPAK signaling activates the Hippo pathway via MAP4K4 on the one hand and promotes pro-invasive signaling via PKCθ on the other hand. Dysregulated STRIPK signaling is involved in cancer progression due to impaired Hippo tumor suppressor pathway activation and increased invasiveness. | (62, 66) |
| STRIP1 | MAP4K4 interacts with STRIP1, a component of the STRIPAK complex. STRIP1 is involved in MAP4K4 repression via PP2A. | (62, 66) |
| TRAF2 | MAP4K4 downregulates IL-6 production in T cells through direct phosphorylation and degradation of TNF receptor-associated factor 2 (TRAF2), leading to the suppression of Th17 cell-mediated insulin resistance in vivo. | (25) |
| Ubiquitin | MAP4K4/6/7 kinases phosphorylate ubiquitin in cells at low extracellular matrix stiffness, leading to decreased DNA repair and increased sensitivity to DNA-damaging agents. | (81) |
| VASP | MAP4K4 phosphorylates VASPS157. S157 phosphorylation depends on MAP4K4 interaction with STRN3 via the CNH domain and is associated with cell invasiveness. | (62) |
Table summarizing activators and effectors of MAP4K4 and the biological function of their interaction with MAP4K4.