Ras and relatives—job sharing and networking keep an old family together

Phylogenetic tree of Ras family members. Human (no suffix) and C. elegans (Ce suffix) Ras sequences were obtained from the NCBI and WormBase (www.wormbase.org) databases and aligned using the ClustalW program at the European Bioinformatics Institute (www.ebi.ac. uk/clustalw). The alignment was then analyzed with PHYLIP at www. genebee.msu.su/services/phtree_full.html with the max/min factor for the cluster algorithm set to 255 and to 8 for the topological algorithm.

Differential trafficking and membrane localization of Ras proteins with palmitoylated or polybasic carboxy-termini. As shown in references , prenylation occurs in the cytoplasm followed by proteolysis of the last three amino acids on Ras proteins (indicated by -aaX) on the endoplasmic reticulum (ER) membrane. After methylesterfication (indicated by +CH3), isoforms with stretches of basic residues near their C-termini take a relatively undefined route to the disordered plasma membrane that may involve microtubules (indicated by tubulin?). Other isoforms that are palmitoylated on cysteine residues near their C-termini traffic through the Golgi to lipid raft areas by the conventional exocytic pathway. Receptors present in lipid rafts or in the disordered membrane may hypothetically activate Ras proteins colocalized in these areas preferentially (indicated by ? on the arrows from receptors to Ras molecules).

Schematic representation of Ras family guanine nucleotide exchange factors with their domain organization. RasGEF, domain with homology to the catalytic domain of CDC25 exhibiting GEF activity toward Ras subfamily proteins. RhoGEF, domain with homology to the catalytic domain of Dbl exhibiting GEF activity towards Rho subfamily proteins. PH, pleckstrin homology. P, poly-proline–rich sequences, representing SH3 (Src homology 3) domain binding sites. IQ, calmodulin binding. DAG, diacylglycerol binding. DEP, domain found in Dishevelled (Dvl) proteins. RA, Ras association. PDZ, domain found in PSD95, Dlg, ZO1 proteins. SH2, Src homology 2 domain, phosphotyrosine binding. X,Y: phospholipase catalytic domains. C2, calcium-dependent lipid binding domain. a, RasGRP4 features only one EF hand. b, Epac1 lacks the N-terminal cNMP binding domain present in Epac2. c, RA-GEF II has a longer N- but shorter C-terminus than RA-GEF I. d, the cNMP domains of RA-GEF I/II do not interact with cAMP or cGMP. e, Rgl3/RPM is the only protein of the RalGDS/Rgl families with a proline-rich region.

General downstream effectors of Ras proteins and their functions.