JAKperheen

The JAK family, known in Finnish as JAK-perheen, comprises a group of cytoplasmic non-receptor protein tyrosine kinases that transduce signals from many cytokine receptors to the nucleus via the JAK-STAT pathway. They are essential for hematopoiesis, immune responses, and regulation of inflammation.

The family includes four members: JAK1, JAK2, JAK3, and TYK2. All share a conserved domain structure that begins with a FERM domain for receptor association, followed by an SH2-like domain, a regulatory pseudokinase domain (JH2), and a catalytic kinase domain (JH1). They associate with type I and II cytokine receptors, enabling signal propagation upon receptor engagement.

Mechanistically, cytokine binding to its receptor activates associated JAKs, which phosphorylate each other and the receptor. This creates docking sites for STAT transcription factors, which are then phosphorylated by JAKs. Phosphorylated STATs dimerize and translocate to the nucleus to regulate gene expression, shaping immune responses, cell proliferation, and differentiation.

Clinical significance is broad. Aberrant JAK signaling is implicated in myeloproliferative neoplasms, notably through the JAK2 V617F mutation, and in various inflammatory and autoimmune conditions. JAK3 deficiency causes a severe combined immunodeficiency in some cases. Pharmacological inhibitors of JAKs, such as ruxolitinib (JAK1/2 inhibitor), baricitinib (JAK1/2), and tofacitinib (JAK1/3), are used to treat certain hematologic disorders and autoimmune diseases, though they carry risks such as immunosuppression and infection.

The JAK family remains central to understanding cytokine signaling and as a therapeutic target in multiple diseases, with ongoing research to refine selectivity and safety of JAK inhibitors.