H-ras, N-ras, and K-ras are canonical ras gene family members frequently 
activated by point mutation in human cancers and coding for 4 different, highly 
related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). Their expression 
is nearly ubiquitous and broadly conserved across eukaryotic species, although 
there are quantitative and qualitative differences of expression depending on 
the tissue and/or developmental stage under consideration. Extensive functional 
studies have determined during the last quarter century that these Ras gene 
products are critical components of signaling pathways that control eukaryotic 
cell proliferation, survival, and differentiation. However, because of their 
homology and frequent coexpression in various cellular contexts, it remained 
unclear whether the different Ras proteins play specific or overlapping 
functional roles in physiological and pathological processes. Initially, their 
high degree of sequence homology and the observation that all Ras isoforms share 
common sets of downstream effectors and upstream activators suggested that they 
were mostly redundant functionally. In contrast, the notion of functional 
specificity for each of the different Ras isoforms is supported at present by an 
increasing body of experimental observations, including 1) the fact that 
different ras isoforms are preferentially mutated in specific types of tumors or 
developmental disorders; 2) the different transforming potential of transfected 
ras genes in different cell contexts; 3) the distinct sensitivities exhibited by 
the various Ras family members for modulation by different GAPs or GEFs; 4) the 
demonstration that different Ras isoforms follow distinct intracellular 
processing pathways and localize to different membrane microdomains or 
subcellular compartments; 5) the different phenotypes displayed by genetically 
modified animal strains for each of the 3 ras loci; and 6) the specific 
transcriptional networks controlled by each isoform in different cellular 
settings.