RPS6KC1

RPS6KC1 Full Name

ribosomal protein S6 kinase, 52kDa, polypeptide 1

RPS6KC1 Introduction

RPS6KC1 is an unusual member of the RSK family. Full-length cDNA is about 4.2 kb. ORF encodes a protein of 469 amino acids, the predicted molecular mass of the protein is about 118.7 kDa. The protein has a number of functional domains, such as N-terminal PX (Phox homology) domain, MIT domain and two tandem serine/threonine kinase-like domains (STK1 and STK2). This gene is ubiquitously expressed, with the highest levels of transcripts in brain, testes and heart.

RPS6KC1 has a rather "kinase-independent" mode of regulation. In addition to being catalytically inactive, the protein can associate with multiple other proteins in signaling networks through its domain-mediated protein-protein interactions. Its PX domain binds phosphatidylinositol-3-phosphate (PI3P) and thereby mediates its recruitment to the endosomal membrane, and the MIT domain is involved in interaction with the TRIM family of proteins which are important for the regulation of protein homeostasis. The most striking functional feature, however, is the ability of RPS6KC1 to serve as a scaffold protein. RPS6KC1 can directly bind to sphingosine kinase as well as the antioxidant protein PRDX3 to synchronize the sphingosine-1-phosphate (S1P) signaling pathway with the response to oxidative stress. The protein has also been implicated in modulating neurogenesis and embryonic development in the brain through regulation of the S1P signaling pathway during brain development. As a possible downstream effector of the mTOR signaling pathway, the activity of RPS6KC1 could also be under the control of mTORC1 complex, but the phosphorylation sites and the mechanistic roles of upstream kinases (for example, PDK1) have yet to be characterized.

In cancer research, RPS6KC1 has been identified as a potential oncogene, with somatic mutations frequently detected in breast, ovarian, and lung cancers. Gain-of-function variants could also be involved in tumour cell growth and survival e.g. by having oncogenic effects via dysregulated S1P survival signalling or by abolishing PRDX3-dependent antioxidant functions. Clinical translational studies also suggest that RPS6KC1 overexpression is associated with malignant phenotype and poor overall survival in head and neck squamous cell carcinoma (HNSCC) and may be a diagnostic biomarker and potential therapeutic target in HNSCC. RPS6KC1 has also been shown to cause a neurodevelopmental disorder. Loss-of-function variants (biallelic or dominant negative) in RPS6KC1 have been validated to cause complex neurodevelopmental disorders. Phenotypes associated with RPS6KC1 disease include structural brain abnormalities, cortical dysplasia, and corpus callosum abnormalities.

Figure 1. The mechanism through which PRS6KC1 mitigates ferroptosis and enhances Enz resistance by recruiting PRDX3. (Source: Ji FH, et al. 2025)

Alternate Names for RPS6KC1

RPS6KC1; ribosomal protein S6 kinase, 52kDa, polypeptide 1; ribosomal protein S6 kinase, 52kD, polypeptide 1; ribosomal protein S6 kinase delta-1; humS6PKh1; S6K-delta-1; SPHK1-binding protein; 52 kDa ribosomal protein S6 kinase; ribosomal S6 kinase-like protein with two PSK domains 118 kDa protein; RPK118

• 1. Ji FH, et al. Targeting RPS6KC1 to overcome enzalutamide resistance in prostate cancer. Biomark Res. 2025 Aug 23;13(1):109.
  2. Hayashi S, et al. Identification and characterization of RPK118, a novel sphingosine kinase-1-binding protein. J Biol Chem. 2002 Sep 6;277(36):33319-24.