CASP2

CASP2 Full Name

caspase 2, apoptosis-related cysteine peptidase

CASP2 Introduction

Caspase-2 (CASP2), a member of the cysteine-aspartic protease family, is recognized for its pivotal role in programmed cell death and cellular stress responses. Unlike many other caspases, CASP2 has historically been considered an "orphan" caspase because, although it can trigger apoptosis, its necessity in the apoptotic pathway has been debated. Emerging studies, however, reveal that CASP2 exerts a broader influence beyond apoptosis, including regulation of cell cycle checkpoints, DNA damage responses, and maintenance of genomic stability. Through selective cleavage of cellular substrates, CASP2 functions as a molecular switch that integrates stress signals and can either promote cell death or preserve cell integrity depending on context.

Functionally, CASP2 serves as both a tumor suppressor and a mediator of non-apoptotic cellular processes. Its involvement in safeguarding genomic integrity highlights its importance in preventing malignant transformation, as it can induce cell cycle arrest or apoptosis in response to DNA damage. Recent studies have also shown that CASP2 expression can be transcriptionally upregulated without concomitant protein translation, demonstrating the complex post-transcriptional regulation that fine-tunes its activity in cancer and normal tissues. This dual regulation emphasizes CASP2's role not merely as an executioner of apoptosis but as a critical regulator of cell fate decisions in response to diverse cellular stressors.

Clinically, CASP2 dysfunction has been implicated in a variety of human diseases, ranging from cancer to neurodevelopmental disorders. Biallelic truncating mutations in CASP2 have been linked to severe neurodevelopmental defects including lissencephaly, highlighting its essential role in brain development. In oncology, CASP2 modulates the immune microenvironment and therapeutic responses, particularly in hepatocellular carcinoma and esophageal adenocarcinoma, where it functions within complex gene networks involving apoptosis, DNA repair, cell cycle control, and tumor suppression. These findings position CASP2 as a promising therapeutic target for cancer treatment and a critical biomarker for disease progression and cellular stress adaptation.

Alternate Names for CASP2

CASP2; caspase 2, apoptosis-related cysteine peptidase; ICH1; NEDD2; CASP-2; NEDD-2; PPP1R57; caspase-2; protease ICH-1; protein phosphatase 1, regulatory subunit 57; neural precursor cell expressed developmentally down-regulated protein 2;

• 1.Brown-Suedel AN, Bouchier-Hayes L. Caspase-2 Substrates: To Apoptosis, Cell Cycle Control, and Beyond. Front Cell Dev Biol. 2020, 8:610022.
  2.Uctepe E, et al.; Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly. Eur J Hum Genet. 2024, 32(1):52-60.