Natural cytotoxicity trigger receptor 2 (NKp44)

Natural cytotoxicity trigger receptor 2 (NKp44) is a type I transmembrane glycoprotein and a key member of the natural cytotoxicity receptor (NCR) family, primarily expressed on activated natural killer (NK) cells and certain innate lymphoid cells like ILC3. Unlike other NCRs such as NKp30 and NKp46, NKp44 is typically absent on resting NK cells and is selectively induced following cytokine stimulation (e.g., IL-2 or IL-15), making it a hallmark marker of NK cell activation [6, 10]. It plays a critical role in the innate immune response by recognizing a diverse array of ligands, including tumor-associated molecules like a specific isoform of MLL5 (NKp44L) and pathogen-derived proteins such as viral hemagglutinins [2, 8]. Upon ligand binding, NKp44 typically promotes NK cell-mediated lysis of abnormal cells by signaling through the DAP12 adapter molecule; however, it can also exhibit inhibitory functions when interacting with ligands like proliferating cell nuclear antigen (PCNA) on tumor cells [1, 2]. This dual nature makes NKp44 a complex but promising target in immuno-oncology, where therapeutic strategies aim to either harness its activating potential through bispecific engagers and CAR-NK cells or block its inhibitory interactions to restore anti-tumor immunity [4, 7]. While no specific NKp44-targeting drugs are currently FDA-approved, it remains a central focus for developing next-generation immunotherapies for both solid and hematological malignancies [9, 11].

Other names

NCR2CD336LY95p44 natural killer cell receptorLymphocyte antigen 95 homologNatural killer cell p44-related protein

NKp44 functions primarily by triggering natural killer (NK) cell cytotoxicity and cytokine release (such as IFN-gamma) upon binding to specific ligands on target cells. It signals through the association with the ITAM-containing adapter molecule DAP12 (KARAP). In some contexts, it can also mediate inhibitory signals when interacting with certain ligands like PCNA, leading to immune evasion by tumor cells.