MAP3K1

MAP3K1 Full Name

mitogen-activated protein kinase kinase kinase 1, E3 ubiquitin protein ligase

MAP3K1 Introduction

MAP3K1 (also called MEKK1) is a large multidomain serine/threonine kinase that functions at the apex of multiple MAPK cascades, with well-characterized roles in JNK and ERK5 activation and an emerging role as a regulator of NF-κB signaling. The protein contains an N-terminal RING domain that has E3 ubiquitin ligase activity, a central kinase domain, and a C-terminal region that mediates interactions with the cytoskeleton and with various MAP2Ks. The MAP3K1 gene maps to chromosome 5q11.2 and is broadly expressed.

Figure 1. The structure of MAP3K1.

Hub Kinase Linking Cytoskeletal, MAPK, and NF-κB Pathways
Through its kinase domain, MAP3K1 phosphorylates MAP2K4 and MAP2K7 to engage the JNK pathway, and MAP2K5 to engage ERK5, integrating diverse upstream signals into specific MAPK outputs. The N-terminal RING domain of MAP3K1 ubiquitinates targets including the NF-κB inhibitor IκBα, allowing NF-κB activation in response to TNFα and other pro-inflammatory cytokines. MAP3K1 also binds the actin cytoskeleton through a C-terminal coiled-coil region, and this interaction localizes MAP3K1 activity to sites of mechanical stress where it modulates integrin signaling and cell migration.

Breast Cancer and Estrogen Receptor Signaling
Somatic mutations in MAP3K1 are among the most common genetic alterations in estrogen-receptor-positive breast cancer, with loss-of-function mutations identified in roughly 10% of tumors. These mutations disrupt MAP3K1-mediated negative feedback on estrogen receptor signaling, leading to enhanced ER transcriptional output and tamoxifen resistance in some studies. MAP3K1 mutations also cooperate with PIK3CA alterations in breast tumorigenesis, and germline truncating variants in MAP3K1 have been associated with familial breast cancer risk, placing the kinase at the center of precision oncology efforts in luminal disease.

Alternate Names for MAP3K1

MAP3K1; mitogen-activated protein kinase kinase kinase 1, E3 ubiquitin protein ligase; MEKK; MEKK1; SRXY6; MEKK 1; MAPKKK1; mitogen-activated protein kinase kinase kinase 1; MEK kinase 1; MAP/ERK kinase kinase 1; MAPK/ERK kinase kinase 1;