Phosphoinositide 3-kinase (PI3K) enzyme plays a vital role in the insulin signaling pathway as well as in other pathways that are involved in the growth, migration, and survival of cells. In the insulin signaling pathway, PI3K proteins that include p50α, p85α, p85β, p55γ, p110α, p110β, and p110γ are associated with the critical node-2. This study has used bioinformatic tools to understand phylogenetics, conservation patterns, conserved domains, orientation of residues, and interactions among PI3K proteins. The phylogenetic analysis showed p110α and p110γ with a common origin while p50α and p85α sharing an evolutionary history. The sequence alignment showed the highest score (97) between p85α and p50α. Several highly conserved amino acid residues were found high in p110 beta (n = 102). Subsequently, the number of highly conserved amino acid restudies was low in p50alpha and p55γ (n = 15). The PI3K proteins are evidentially linked to other proteins and pathways as well.