NKF4 (new kinase family 4) is a member of the Ser/Thr kinase (STK) family and is classified as the "other" group in the human kinome. The NKF4 family mainly includes STK35L1, which is a human protein composed of Amino acid kinase 35) gene coding. According to a study showing that STK35L1 is overexpressed with two proteins in osteosarcoma cells, STK35 is associated with CLP36, so STK35L1 is named Clik1 (CLP36 interaction kinase 1). The Clik1 gene described by Vallenius et al. Encodes a 501 amino acid protein. Later, Goyal et al. The coding sequence of STK35 gene was found to be incomplete. The newly identified STK35 gene sequence encodes a protein of 534 amino acids with an N-terminal extension of 133 amino acids. It has been designated as STK35L1.
Protein kinases mediate signal transduction in eukaryotic cells and are involved in regulating all cellular processes, such as transcription, translation, cell cycle processes, cytoskeletal rearrangement, migration, apoptosis, and differentiation. Eukaryotic protein kinases that phosphorylate serine/threonine (Ser/Thr) or tyrosine (Tyr) residues are the largest enzyme superfamily, accounting for about 1.7% of all human genes. Since completing the first draft of the human genome sequence, various groups have estimated the number of human kinases to be 448, 510, and 518 based on the methods and data sets used in the analysis. The regulatory domain of most protein kinases is located at the C-terminus and N-terminus of the kinase domain. Despite their different substrate specificities, the kinase domains of Ser/Thr- and Tyr-kinase are highly conserved and consist of two leaves with a total length of approximately 275 amino acids. The catalytic domain is characterized by a series of short sequence motifs that define 11 subdomains and serve as key elements in the catalytic core of the kinase domain. These motifs in combination with overall catalytic domain sequences can be used to identify genes encoding protein kinases in the genome by various methods, such as sequence alignment and hidden Markov model search. This analysis and the corresponding cDNA sequence information can predict the number of protein kinases in different genomes. Human kinome has more than 100 unidentified kinases, whose substrates and biological functions are unknown. STK35 and its homolog PDIK1L (similar to PDLIM1 (CLP36) interacting kinase 1) share 69% protein sequence identity in the kinase domain.
They are members of the NKF4 (new kinase family 4) Ser/Thr kinase (STK) family and are classified as "other" groups in the human kinome. In the Kinomer database, the best match for the STK35 kinase sequence was in the TKL group. According to a study, after overexpression of two proteins in osteosarcoma cells, there is an association between STK35 and CLP36, so STK35 is also known as Clik1 (CLP36 interaction kinase 1). CLP36 is an α-actin binding protein, it contains a LIM domain and a PDZ domain, and is mainly located on stress fibers. Therefore, a possible function of STK35 in the regulation of actin cytoskeleton was proposed. The biological function and substrate of STK35 are unknown. The STK35 gene was found to be particularly up-regulating in colorectal cancer. In rodent models of Parkinson's disease, the expression of STK35 gene has changed. Genome-wide RNAi screening revealed that STK35 silencing was the first five hits that led to a reduction in liver cell infection by Plasmodium berghei sporozoites. These studies indicate that STK35 may play a role in various human diseases and deserve immediate attention from scientists in the fields of biology and medicine.
STK35L1 is mainly found in the nucleus and nucleoli. Nuclear actin was identified as a novel binding partner for STK35L1. However, it can interact with PDLIM1/CLP-36 in the cytoplasm and localize to actin stress fibers. STK35L1 regulates the expression of CDKN2A and inhibits the transition from G1 to S phase. Consumption of STK35L1 by siRNA impairs endothelial cell migration. STK35L1 can serve as a central kinase linking the cell cycle and endothelial cell migration.