KLK6

What is KLK6 protein?

KLK6 gene (kallikrein related peptidase 6) is a protein coding gene which situated on the long arm of chromosome 19 at locus 19q13. This gene encodes a member of the kallikrein subfamily of the peptidase S1 family of serine proteases. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. The encoded preproprotein is proteolytically processed to generate the mature protease. Expression of this protease is regulated by steroid hormones and may be elevated in multiple human cancers and in serum from psoriasis patients. The encoded protease may participate in the cleavage of amyloid precursor protein and alpha-synuclein, thus implicating this protease in Alzheimer's and Parkinson's disease, respectively. The KLK6 protein is consisted of 244 amino acids and its molecular mass is approximately 26.9 kDa.

What is the function of KLK6 protein?

KLK6 is active against a variety of proteins, including amyloid precursor protein, myelin basic protein, gelatin, casein, and extracellular matrix proteins such as fibronectin, laminin, fibronectin, and collagen. In addition, KLK6 was able to degrade alpha-synuclein and prevent its aggregation, suggesting that it may be involved in the pathogenesis of Parkinson's disease and other synuclein diseases. KLK6 may also be involved in regulating axonal growth after spinal cord injury.

Fig1. Potential roles for KLK6-mediated invasion and migration in PDAC. (Leran Zhang, 2022)

KLK6 Related Signaling Pathway

KLK6 is highly upregulated in a variety of cancers, and its increased activity promotes cancer invasion and metastasis. Overexpression of KLK6 is found in breast cancer cell lines and increases the growth and metastasis of primary tumors. Transfection and overexpression of KLK6 increased the invasion ability of colon cancer cells in vitro via TGFβ and SMAD signaling pathways. Probes of KLK6 activity were used to reveal the role of KLK6 activity in pancreatic cancer cell invasion, and KLK6 inhibitors were combined with n-terminal omics to identify potential secreted protein substrates of KLK6 in PDAC cells.

KLK6 Related Diseases

KLK6 function in tumor cells suggests that it may play a role in tumor invasion and metastasis. Tumor cells treated with neutralizing KLK6 antibodies migrated less than control cells, suggesting that KLK6 may play a role in tumor invasion and metastasis. In addition, KLK6 expression is upregulated in a variety of human cancers, including colorectal cancer, and is associated with poor prognosis in colorectal cancer. In colorectal cancer, high expression of KLK6 is associated with the aggressive phenotype of tumors and may promote the proliferation of colorectal cancer cells by activating protease activating receptor 2 (PAR2).

Bioapplications of KLK6

KLK6 is an important bioactive protein, and related biological reagents are relatively complete, including KLK6 antibody, KLK6 elisa, which is used to detect the expression and distribution of the protein. The KLK6 fuse protein is also widely used in biological research, where it has been used to study the function and cellular effects of KLK6.

Case Study 1: Leran Zhang, 2022

Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, researchers developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M-1 s-1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases.

Fig1. 2D illustration of IMP-2352 and its interactions with KLK6.

Fig2. KLK6 blot of a pulldown experiment.

Case Study 2: Jingyi Song, 2018

Colorectal cancer is one of the most common types of malignancies worldwide, and as it is often diagnosed at an advanced stage, it is a serious threat to human health. MicroRNAs are important regulators of the growth and metastasis of colon cancer (CC). In the present study, the results demonstrated that kallikrein‑related peptidase 6 (KLK6) plays a critical role in suppressing colon carcinoma progression. To further investigate whether microRNAs affect the impact of KLK6, a bioinformatics approach was employed, which indicated that let‑7i‑5p may directly target KLK6. Furthermore, the expression level of let‑7i‑5p was significantly negatively correlated with the expression of KLK6 at the mRNA and protein levels in CC. Functionally, overexpression of let‑7i‑5p inhibited the proliferation and invasion of CC cells, and suppressed the growth of CC in vitro. The luciferase reporter assays revealed that let‑7i‑5p targeted the KLK6 3'‑untranslated region. Collectively, these results indicated that let‑7i‑5p inhibited the proliferation and metastasis of CC cells by targeting KLK6, thereby blocking the cell cycle and promoting apoptosis in colon cells.

Fig3. Results of luciferase activity assay indicated that KLK6 directly targets Let-7i-5p.

Fig4. Western blotting was performed to detect the protein expression levels.

KLK6 has several biochemical functions, for example, protein binding,serine-type endopeptidase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by KLK6 itself. We selected most functions KLK6 had, and list some proteins which have the same functions with KLK6. You can find most of the proteins on our site.

KLK6 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with KLK6 here. Most of them are supplied by our site. Hope this information will be useful for your research of KLK6.

pheserargamc;COL1A1;COL4A1;COL1A2;FGA;FGB;APP;COL4A2;COL4A5;CSN1S1;COL4A4;COL4A3;COL4A6