STK4 Gene

The STK4 gene (STK4 stands for "serine/threonine kinase 4") is a protein-coding gene located on chromosome 20q13.12. The protein encoded by this gene is a cytoplasmic kinase (it is structurally similar to yeast Ste20p kinase) that phosphorylates myelin basic protein. The enzyme undergoes autophosphorylation. A fragment of the encoded protein cleaved by caspase has been shown to phosphorylate histone H2B. Phosphorylation catalyzed by this protein has been associated with apoptosis (Jørgensen SE et al. 2021).

The encoded "serine-threonine kinase 4" is a key component of the Hippo signaling pathway that plays a central role in controlling organ size and tumor suppression by limiting proliferation and promoting apoptosis. The core of this pathway consists of a kinase cascade in which STK3/MST2 and STK4/MST1 in complex with their regulatory protein SAV1 phosphorylate and activate LATS1/2 in complex with their regulatory protein MOB1, which in turn phosphorylates and inactivates the oncoprotein YAP1 and WWTR1/TAZ.

STK3 and STK4 are required to suppress proliferation of mature hepatocytes, prevent activation of facultative adult liver stem cells (oval cells), and inhibit tumor formation.

Serine-threonine kinase 4 phosphorylates FOXO3 upon oxidative stress, leading to its nuclear translocation and initiation of cell death.

Furthermore, serine threonine kinase phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T).

Diseases associated with STK4 include:

• T-cell immunodeficiency with recurrent infections and autoimmunity with or without cardiac malformations and lung cancer (T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations; OMIM: 614868) (Nehme NT et al. 2012; Abdollahpour H et al. 2012).

Associated signaling pathways include sweet key signaling and cytoskeletal signaling.

1. Abdollahpour H et al. (2012) The phenotype of human STK4 deficiency. Blood 119: 3450-3457.
2. Jørgensen SE et al (2021) STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling. J Clin Immunol 41:109-124.
3. Nehme NT et al (2012) MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119: 3458-3468.