Cyclin-dependent kinase 6-cyclin D3 complex (CDK6-cyclin D3)

The Cyclin-dependent kinase 6-cyclin D3 complex (CDK6-cyclin D3) is a heterodimeric serine/threonine kinase that serves as a master regulator of the G1 to S phase transition in the cell cycle [1, 11]. While CDK4 and CDK6 are often considered functionally redundant, the CDK6-cyclin D3 complex possesses unique roles, particularly in hematopoietic cell development and the survival of certain malignancies like T-cell acute lymphoblastic leukemia (T-ALL) [3, 7]. Beyond its canonical role in phosphorylating the retinoblastoma protein (RB1) to drive cell cycle progression, this complex also regulates cellular metabolism by phosphorylating and inhibiting glycolytic enzymes such as 6-phosphofructokinase (PFKP) and pyruvate kinase M2 (PKM2) [1, 9]. This metabolic rewiring redirects intermediates into the pentose phosphate pathway, increasing antioxidant production and protecting tumor cells from apoptosis induced by reactive oxygen species [1, 2]. In clinical practice, this complex is a primary target for CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib, which are widely used to treat hormone receptor-positive breast cancer [10, 12]. High expression levels of the CDK6-cyclin D3 complex are associated with increased sensitivity to these inhibitors, potentially leading to tumor regression rather than just growth arrest [4, 9]. However, therapeutic use is often limited by safety concerns such as neutropenia and leukopenia, which result from the inhibition of CDK6 in bone marrow progenitors [12].

Other names

CDK6-CCND3 complexCyclin D3-CDK6 kinaseSerine/threonine-protein kinase 6-cyclin D3 complexPLSTIRE-cyclin D3 complex

ATP-competitive inhibition of the kinase activity of the CDK6-cyclin D3 complex, which prevents the phosphorylation of the retinoblastoma protein (RB1) and metabolic enzymes such as PFKP and PKM2, leading to G1 cell cycle arrest and induction of apoptosis in specific tumor contexts [1, 6, 11].