RPS6KA2

RPS6KA2 Full Name

ribosomal protein S6 kinase, 90kDa, polypeptide 2

RPS6KA2 Introduction

Ribosomal protein S6 kinase, 90 kDa, polypeptide 2 (RPS6KA2), also known as RSK3, is a serine/threonine protein kinase that functions as a key downstream effector of the MAPK/ERK signaling pathway. Encoded by the RPS6KA2 gene, RSK3 belongs to the p90 ribosomal S6 kinase (RSK) family, which also includes RSK1, RSK2, and RSK4. Unlike many protein kinases, RSK3 contains two functional kinase domains that are activated through sequential phosphorylation events following ERK stimulation, enabling precise control of intracellular signaling. Although the four RSK isoforms share a conserved structural framework, accumulating evidence shows that RSK3 has distinct biological functions, tissue-specific expression patterns, and substrate preferences. These characteristics make RPS6KA2 an increasingly important research target for understanding signal transduction, kinase regulation, and the development of isoform-selective therapeutic strategies.

RPS6KA2 regulates a broad range of cellular processes by phosphorylating proteins involved in transcription, cell-cycle progression, protein synthesis, apoptosis, differentiation, and stress responses. As an ERK-responsive kinase, RSK3 integrates extracellular growth signals and coordinates multiple signaling networks that determine cell fate. Beyond its established role in MAPK signaling, recent studies have demonstrated that RSK3 directly interacts with IκBα to modulate NF-κB activation, revealing previously unrecognized crosstalk between these major signaling pathways. RPS6KA2 has also been implicated in the regulation of autophagy, ferroptosis, and survival signaling, highlighting its importance in maintaining cellular homeostasis under both physiological and pathological conditions. Because of its diverse downstream substrates and context-dependent functions, RPS6KA2 is widely investigated in kinase biology, cancer signaling, and targeted drug discovery.

Altered expression or activity of RPS6KA2 has been associated with several human malignancies and therapeutic resistance. In many tumor types, including ovarian, breast, prostate, pancreatic, and glioblastoma models, reduced RPS6KA2 expression has been linked to disease progression or impaired treatment response, supporting its potential tumor-suppressive role in specific cellular contexts. Recent research has identified the miR-512-3p/RPS6KA2 regulatory axis as a key mechanism driving cisplatin resistance in ovarian cancer through modulation of autophagy and ferroptosis. Other studies have shown that RSK3-mediated activation of NF-κB promotes breast cancer cell proliferation, migration, and survival, while disruption of the RSK3–IκBα interaction suppresses tumor growth and enhances apoptosis. In prostate cancer, RSK family members, including RPS6KA2, contribute to MAPK/ERK-dependent signaling associated with tumor progression and resistance to hormone and chemotherapy. Together, these findings establish RPS6KA2 as a clinically relevant kinase with growing value as a biomarker, a therapeutic target, and a promising focus for precision oncology and targeted kinase inhibitor development.

Alternate Names for RPS6KA2

RPS6KA2; ribosomal protein S6 kinase, 90kDa, polypeptide 2; RSK; HU-2; RSK3; p90-RSK3; pp90RSK3; MAPKAPK1C; S6K-alpha; S6K-alpha2

• 1.Wright EB, Lannigan DA. Therapeutic targeting of p90 ribosomal S6 kinase. Front Cell Dev Biol. 2023, 11:1297292.
  2.Cronin R, et al.; The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance. Oncogene. 2021, 40(22):3775-3785.