Invasion of T-lymphoma cells: cooperation between Rho family GTPases and lysophospholipid receptor signaling.
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.
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
J C
JC
Stam
F
F
Michiels
R A
RA
van der Kammen
W H
WH
Moolenaar
J G
JG
Collard
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000199:Actins; D000818:Animals; D001769:Blood; D001905:Botulinum Toxins; D002118:Calcium; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D048429:Cell Size; D003599:Cytoskeleton; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D016399:Lymphoma, T-Cell / Q000473:pathology*; D008246:Lysophospholipids / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D011493:Protein Kinase C / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011554:Pseudopodia; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
D000199:Actins; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; D009363:Neoplasm Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; C060506:sphingosine 1-phosphate; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D011493:Protein Kinase C; D010738:Type C Phospholipases; D001905:Botulinum Toxins; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D013110:Sphingosine; D002118:Calcium