The KRAS gene encodes
two isoforms, KRas4a and KRas4b. Differences
in the signaling functions of the two KRas proteins are poorly understood.
Here we report the comparative and nucleotide-dependent interactomes
of KRas4a and KRas4b. Many previously unknown interacting proteins
were identified, with some interacting with both isoforms while others
prefer only one. For example, v-ATPase a2 and eIF2Bδ interact
with only KRas4b. Consistent with the v-ATPase interaction, KRas4b
has a significant lysosomal localization. Comparing WT and constitutively
active G12D mutant KRas, we examined differences in the effector proteins
of the KRas4a and KRas4b. Interestingly, KRas4a binds RAF1 stronger
than KRas4b. Correspondingly, KRas4a can better promote ERK phosphorylation
and anchorage-independent growth than KRas4b. The interactome data
represent a useful resource to understand the differences between
KRas4a and KRas4b and to discover new function or regulation for them.
A similar proteomic approach would be useful for studying numerous
other small GTPases