PI3Klike

PI3Klike is a descriptive term used in biochemistry and genomics to refer to enzymes that resemble phosphoinositide 3-kinases (PI3Ks) in their catalytic domain. The term is not a formal protein family name; rather, it groups proteins whose catalytic cores share similarity to the PI3K fold. PI3Klike proteins can include bona fide lipid kinases as well as members of the PI3K-related kinase (PIKK) family that function as protein kinases.

Structural and evolutionary features: PI3Klike proteins typically contain a catalytic kinase domain with motifs conserved among the PI3K/PIKK superfamily. In lipid-kinase members, the domain catalyzes ATP-dependent phosphorylation of phosphatidylinositol lipids on the 3-position, generating lipid second messengers that recruit cytosolic effectors. In protein-kinase members of the PIKK branch, the domain targets serine/threonine residues on substrate proteins and operates within large multi-subunit signaling complexes linked to DNA damage response and genome stability.

Examples and scope: Canonical lipid-PI3Ks (Class I-III) fall under the broad umbrella, as do PI3K-related kinases such as ATM, ATR, and DNA-PKcs. Although both groups share the PI3K-like catalytic fold, they differ in substrates, cellular roles, and regulatory architectures.

Function and clinical relevance: PI3Klike activity influences cell growth, metabolism, and survival via lipid signaling pathways, or genome integrity through DNA damage signaling. Dysregulation of PI3K-like activities is associated with cancer and other diseases. Pharmacological inhibitors targeting lipid-PI3Ks are widely studied and used clinically, while inhibitors of PIKK family members are investigated as adjuvants to radiotherapy or chemotherapy.