The Multifaceted Role of STK35/STK35L1 in Human Diseases: A Time for Critical Appraisal

Dysregulation of protein kinases is associated with developmental defects and various human diseases. The human kinome comprises 518 kinases, including several orphan kinases whose functions remain to be fully characterized. The NKF4 family, which includes STK35L1 and PDIK1L, is one such uncharacterized kinase family. STK35L1, also known as Clik1, was initially identified as a nuclear kinase associated with actin fibers. Subsequent studies have demonstrated that STK35L1 plays critical roles in cellular processes such as cell cycle regulation, migration, angiogenesis, the DNA damage response, and related processes such as spermatogenesis. STK35L1 has also been implicated in various developmental processes and its knockout mice exhibited defects in the testis, ovary, and eye. STK35L1 acts as a central regulator of the fundamental cellular functions, and its dysregulation leads to various diseases. Research has established that STK35L1 regulates tumor growth and proliferation in cancers such as osteosarcoma, colorectal cancer, and acute myeloid leukemia. Notably, it also affects chemosensitivity in colorectal cancer and metabolism in acute myeloid leukemia. Additionally, STK35L1 is crucial for the infection of hepatocytes by Plasmodium sporozoites during the liver stage of Malaria. This review discusses the current understanding of STK35L1, highlighting its role in various diseases.