FMNL2

FMNL2 Full Name

formin-like 2

FMNL2 Introduction

FMNL2 encodes formin-like 2, a member of the diaphanous-related formin family of actin-nucleating proteins that directly catalyze the assembly of unbranched actin filaments. Structurally, FMNL2 contains the hallmark formin domain architecture: an N-terminal GTPase-binding domain (GBD) that mediates interaction with activated Rho GTPases, an autoregulatory diaphanous inhibitory domain (DID), and a C-terminal formin homology 2 (FH2) domain that nucleates actin polymerization and remains processively associated with the elongating barbed end of the filament, together with an FH1 domain that recruits profilin-actin complexes to accelerate filament elongation. Upon release of autoinhibition through binding of RhoC-GTP, FMNL2 drives the assembly of actin filaments that underlie key cellular protrusive structures — including lamellipodia, filopodia, and invadopodia — and thereby governs cell shape, directed migration, and invasive motility. FMNL2 was identified as a specific effector of RhoC that promotes amoeboid-type invasive cell motility, a migration mode characterized by rounded cell morphology and high contractility that enables tumor cells to squeeze through dense extracellular matrix without proteolytic degradation.

Figure 1. Domain organization of the seven mammalian formin subfamilies. (Source: Kawabata Galbraith K, et al. 2019)

In the context of human cancer, FMNL2 is one of the most consistently upregulated formins in epithelial malignancies and has been extensively characterized in colorectal cancer (CRC), where its elevated expression correlates with advanced stage, lymph node metastasis, and poor overall survival. FMNL2 promotes CRC metastasis through multiple interconnected mechanisms: it activates Rho/ROCK-mediated actin assembly and epithelial-mesenchymal transition, and it drives tumor angiogenesis by directly interacting with epidermal growth factor-like protein 6 (EGFL6) through its GBD/FH3 domain, promoting EGFL6 secretion via exosomes and activating the EGFL6/CKAP4/ERK signaling axis in endothelial cells. In vivo, FMNL2 overexpression enhances tumor vascular density, tumor growth, and liver metastasis, while its knockdown produces the opposite effects. FMNL2 overexpression has also been documented in melanoma, diffuse-type gastric cancer, breast cancer, and glioblastoma, and it is negatively regulated by tumor-suppressive microRNAs including miR-137, miR-206, and miR-34a, which impair invasion and metastasis by targeting FMNL2 transcripts. These findings position FMNL2 as a central node linking cytoskeletal dynamics to both invasive migration and tumor microenvironment remodeling, making it an attractive candidate for anti-metastatic therapeutic strategies.

Alternate Names for FMNL2

FMNL2; formin-like 2; FHOD2,formin homology 2 domain containing 2; formin-like protein 2; KIAA1902; FHOD2; Formin homology 2 domain containing protein 2; Formin like protein 2; KIAA1902; OTTHUMP00000204908; formin homology 2 domain containing 2; formin ho

• 1. Kawabata Galbraith K, et al. Multiple roles of the actin and microtubule-regulating formins in the developing brain. Neurosci Res. 2019 Jan;138:59-69.
  2. He G, et al. Formin-like 2 promotes angiogenesis and metastasis of colorectal cancer by regulating the EGFL6/CKAP4/ERK axis. Cancer Sci. 2023 May;114(5):2014-2028.