Drosophila Pico and Its Mammalian Ortholog Lamellipodin Activate Serum Response Factor and Promote Cell Proliferation

Abstract

SummaryMIG-10/RIAM/lamellipodin (MRL) proteins link activated Ras-GTPases with actin regulatory Ena/VASP proteins to induce local changes in cytoskeletal dynamics and cell motility. MRL proteins alter monomeric (G):filamentous (F) actin ratios, but the impact of these changes had not been fully appreciated. We report here that the Drosophila MRL ortholog, pico, is required for tissue and organismal growth. Reduction in pico levels resulted in reduced cell division rates, growth retardation, increased G:F actin ratios and lethality. Conversely, pico overexpression reduced G:F actin ratios and promoted tissue overgrowth in an epidermal growth factor (EGF) receptor (EGFR)-dependent manner. Consistently, in HeLa cells, lamellipodin was required for EGF-induced proliferation. We show that pico and lamellipodin share the ability to activate serum response factor (SRF), a transcription factor that responds to reduced G:F-actin ratios via its co-factor Mal. Genetics data indicate that mal/SRF levels are important for pico-mediated tissue growth. We propose that MRL proteins link EGFR activation to mitogenic SRF signaling via changes in actin dynamics.

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

“…NANOS1 is overexpressed in some human invasive lung carcinomas and increases the production of MT1-matrix metalloproteinase to induce matrix metalloproteinase-dependent invasion of carcinoma cells (26). RAPH1 is known to promote cell proliferation and to play an important role in cell motility (27). To confirm our previous microarray results, we compared expression levels of the CDK6, NEK7, NANOS1, and RAPH1 genes between KDM2A-depleted cells and control siRNA-treated cells using quantitative RT-PCR.…”

The adaptor molecule RIAM integrates signaling events critical for integrin-mediated control of immune function and cancer progression

“…Reduction in pico expression in Drosophila resulted in animals with 1 an overall reduction in body size due to decreased cell growth, whereas ectopic expression of pico promoted coordinated cell growth and proliferation, leading to tissue overgrowth (8). These studies also indicated that the cell proliferative effect of pico in Drosophila is conserved with mammalian MRL proteins, because overexpression of Lpd in human cervical carcinoma (HeLa) cells stimulated EGF-mediated growth.…”

“…Subsequently, mutations in the Drosophila MRL ortholog CG11940 were identified, and the gene was named pico due to the retarded growth phenotype resulting from pico knockdown or loss-of-function mutation (8). Reduction in pico expression in Drosophila resulted in animals with 1 an overall reduction in body size due to decreased cell growth, whereas ectopic expression of pico promoted coordinated cell growth and proliferation, leading to tissue overgrowth (8).…”

A Pathogenic Relationship Between a Regulator of the Actin Cytoskeleton and Serum Response Factor

“…SRF and its target genes have been implicated in promoting cell proliferation (Gauthier-Rouviere et al 1991;Lyulcheva et al 2008;Yamaguchi et al 2009) as well as F-actin accumulation (Chai et al 2004a). Known targets of SRF that are involved with cell proliferation are upregulated in Dstn corn1 cornea (Verdoni et al 2008a) and therefore could be influencing hyperproliferation.…”