sphingosine-1-phosphate and Lymphoma--T-Cell

Rho-like GTPases orchestrate distinct cytoskeletal changes in response to receptor stimulation. Invasion of T-lymphoma cells into a fibroblast monolayer is induced by Tiam1, an activator of the Rho-like GTPase Rac, and by constitutively active V12Rac1. Here we show that activated V12Cdc42 can also induce invasion of T-lymphoma cells. Activated RhoA potentiates invasion, but fails by itself to mimic Rac and Cdc42. However, invasion is inhibited by the Rho-inactivating C3 transferase. Thus, RhoA is required but not sufficient for invasion. Invasion of T-lymphoma cells is critically dependent on the presence of serum. Serum can be replaced by the serum-borne lipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) (10(-7)-10(-6) M), which act on distinct G protein-linked receptors to activate RhoA and phospholipase C (PLC)-Ca2+ signaling. LPA- and S1P-induced invasion is preceded by Rho-dependent F-actin redistribution and pseudopodia formation. However, expression of both V14RhoA and V12Rac1 does not bypass the LPA/S1P requirement for invasion, indicating involvement of an additional signaling pathway independent of RhoA. The PLC inhibitor U-73122, but not the inactive analog U-73343, abolishes invasion. Our results indicate that T-lymphoma invasion is driven by Tiam1/Rac or Cdc42 activation, and is dependent on LPA/S1P receptor-mediated RhoA and PLC signaling pathways which lead to pseudopod formation and enhanced infiltration.

Topics: Actins; ADP Ribose Transferases; Animals; Blood; Botulinum Toxins; Calcium; cdc42 GTP-Binding Protein; Cell Cycle Proteins; Cell Line; Cell Size; Cytoskeleton; Fibroblasts; GTP Phosphohydrolases; GTP-Binding Proteins; Guanine Nucleotide Exchange Factors; Lymphoma, T-Cell; Lysophospholipids; Neoplasm Invasiveness; Neoplasm Proteins; Protein Kinase C; Proteins; Pseudopodia; rac GTP-Binding Proteins; Rats; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; rhoA GTP-Binding Protein; Signal Transduction; Sphingosine; T-Lymphoma Invasion and Metastasis-inducing Protein 1; Tumor Cells, Cultured; Type C Phospholipases