Shc proteins are molecular adaptors, involved in several signal transduction pathways. The conserved amino-to-carboxy terminal order of domains is: PTB to SH2 (both are protein-protein interaction domains). Two C. elegans orthologs with the same modularity have been identified: F54A5.3a and T27F7.2. Since, in all other species, this modularity is the signature of Shc-like proteins, Luzi et al. proposed that F54A5.3a and T27F7.2 correspond to nematode homologs of Shc. We termed these two genes
shc-1 and
shc-2 respectively. 3 deletion alleles are available until now:
shc-1(
ok198),
shc-2(
tm028) and
shc-2(
tm030). The first one is a putative null-mutant, the second and third, abolish only the PTB domain.. In mammals SHC was shown to be involved in several functions such as growth, apoptosis, stress resistance and lifespan. In order to understand if Shc-like proteins play a similar role in worms, we focused our attention on two evolutionarily conserved pathways: a) the Daf-2/Insulin-like pathway, that in worm is responsible for lifespan and stress response, and b) the MAPK/JNK pathway, that among other roles is important for stress resistance from nematodes to mammals. The C. elegans Interactome project has revealed that SHC-1 physically interacts with MEK-1, the homolog of mammalian MKK7, which regulates pathogen resistance through the phosphorylation of PMK-1
(p38) and KGB-1(JNK).. As a first approach we wanted to know whether
shc-1 and
shc-2 are involved in one of these two pathways. Lifespan analysis revealed that the single mutants of
shc-1 or
shc-2 or double mutants, resulted in a shorter lifespan compared to the control. Both
shc-2 alleles result in a less severe phenotype than
shc-1, but did not enhance the phenotype in the double mutant. Testing the shc mutants for enhanced susceptibility to pathogens (esp phenotype) we performed feeding experiments with Pseudomonas aeruginosa. The results showed that
shc-1 (similar to mutants of the MAPK/JNK pathway) was more sensitive to pathogen induced stress than wt. In addition, the absence of SHC-1 in
daf-2 loss of function alleles suppressed their enhanced stress resistance phenotype, but still remained more resistant to pathogens than wt worms, implying the existence of other pathways conferring resistance to pathogens. These could be also controlled by the
daf-2 signaling pathway.. Furthermore we have generated transgenic lines expressing full length SHC-1 under its own putative promoter. This transgene was able to rescue the esp phenotype. Expression analyses revealed that
shc-1 is ubiquitously expressed and downregulated in a
daf-16 mutant background. Our preliminary results indicate that
shc-1 and
shc-2 may play a critical role in lifespan regulation; possibly through regulation of stress response and innate immunity.