KLK9 (kallikrein-related peptidase 9)

2016-09-01 Panagiotis G. Adamopoulos , Andreas Scorilas Affiliation

Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens. 157 01, Panepistimiopolis, Athens, Greece \\\/ ascorilas@biol.uoa.gr

Identity

HGNC

KLK9

LOCATION

19q13.41

LOCUSID

284366

ALIAS

KLK-L3,KLKL3

Abstract

Kallikreins (KLKs) represent the largest cluster of serine peptidases, which is composed of 15 members (KLK1-15). The human kallikrein-related peptidase 9 gene (KLK9), like the rest of the KLK genes, encodes for a trypsin-like serine peptidase. Serine peptidases are a group of protein-cleaving enzymes that contain a serine residue in their active site. Kallikreins constitute a subfamily of serine peptidases that cleave kininogen and release vasoactive peptides (kinins). The human KLK9 gene is located at 19q13.41 and consists of 5 exons and 4 intervening introns. Although KLK9 expression has been detected in various normal human tissues, differences in mRNA and protein expression levels have been observed. Like other KLKs, KLK9 is found differentially expressed in multiple human malignancies. Clinical studies regarding the KLK9 expression analysis in breast cancer tissues have demonstrated that KLK9 mRNA expression possesses significant prognostic ability and therefore could be a strong, independent marker of favorable prognosis in patients with breast cancer. In addition, the prognostic potential of the KLK9 mRNA expression levels in ovarian cancer has been clarified, since patients with KLK9-positive tumors demonstrate significantly longer progression-free and overall survival in comparison with KLK9-negative patients. Finally, KLK9 could serve as a prognostic biomarker for patients diagnosed with high-grade astrocytoma, as its expression level is associated with decreased survival of patients. Although the precise localization and structure of the KLK9 gene has now been fully characterized, its functional roles and connections to human diseases are still incompletely understood and merit further investigation.

DNA/RNA

Detailed structure of the annotated full-length mRNA transcript (NM_005551.4) of the KLK9 gene. The full-length KLK9 mRNA transcript is composed of 5 exons. Exons are depicted as boxes and introns as lines; gray and white boxes represent coding and non-coding exons, respectively. Numbers inside boxes and above lines indicate the length of each exon or intron in nucleotides. Finally, the translation start and stop codons are also shown.

Description

The KLK9 gene consists of 5 exons and 4 intervening introns, spanning a region of 7081 bp genomic DNA.

Transcription

A single mRNA transcript (NM_005551.4) of the KLK9 gene, with a total length of 1438 nucleotides, has been annotated. Expression of the KLK9 gene has been detected in various normal human tissues; still, differences in mRNA and protein expression levels have been observed. In particular, the highest mRNA levels of the KLK9 gene have been detected in stomach and vagina. In addition, KLK9 is expressed in high levels in the brain, cervix, esophagus, and fallopian tube, while normal expression levels are observed in breast, prostate, testis, thymus, thyroid, liver, lung, small intestine, spinal cord, and trachea (Shaw and Diamandis, 2007).
However, recent evidence derived from next-generation sequencing approaches has confirmed the existence of 10 novel alternative KLK9 transcripts (KLK9 v.2 -> v.11) that have already been submitted in GenBank® database (GenBank® accession numbers: KX571238 - KX571247 accordingly).

Pseudogene

Not yet identified.

Proteins

Description

The protein encoded by the KLK9 gene is a kallikrein-related serine protease of 250 amino acid residues, with a calculated molecular mass of 25.6 kDa. Similar to other tissue kallikreins, the KLK9 protein is produced as a pre-proenzyme consisting of 250 amino acids, which is processed into a mature form with enzymatic activity (229 amino acids). In addition, KLK9 protein harbors a signal peptide of 19 amino acid residues and a 3-aa pro-segment (Yousef and Diamandis, 2000).

Localisation

KLK9 is mainly localized in the cytoplasm.

Function

Like the rest of the KLK genes, the KLK9 gene encodes for a trypsin-like serine peptidase. Serine peptidases are a group of protein-cleaving enzymes that contain a serine residue in their active site. Kallikreins constitute a subfamily of serine peptidases that cleave kininogen and release vasoactive peptides (kinins) (Schachter, 1980).

Homology

Homology tests have demonstrated that human KLK9 protein shares the highest homology with human KLK11 (40%). In addition, KLK9 protein sequence is 38% homologous with the sequence of KLK5 and 33% homologous with the one of tissue kallikrein ( KLK1) (Yousef and Diamandis, 2000).

Mutations

Note

No germinal or somatic mutations have been associated with cancer.

Implicated in

Top note

No cytogenetic abnormalities have been identified so far.

Entity name

Breast cancer

Prognosis

Clinical studies regarding the expression analysis of the KLK9 gene in breast cancer tissues have demonstrated that KLK9 mRNA expression possesses strong prognostic ability. In particular, breast cancer patients with KLK9-positive tumors exhibit significantly longer disease-free survival (DFS) as well as overall survival (OS) compared to those who are KLK9-negative. As a result, mRNA overexpression of the KLK9 gene in breast tumors is found to be associated with increased DFS and OS leading to the conclusion that KLK9 mRNA levels could be a strong, independent marker of favorable prognosis in breast cancer (Yousef et al., 2003).

Entity name

Ovarian cancer

Prognosis

Similar studies regarding the KLK9 mRNA expression analysis in ovarian tumor samples have clarified the prognostic potential of the KLK9 gene in ovarian cancer. KLK9 mRNA overexpression can serve as an independent favorable prognostic marker for ovarian cancer patients, since patients with KLK9-positive tumors demonstrated significantly longer progression-free and overall survival in comparison with KLK9-negative patients (Yousef et al., 2001).

Entity name

Astrocytoma

Prognosis

KLK9 protein expression analysis in two distinct tissue microarrays containing grade III and IV astrocytoma samples revealed that increased KLK9 expression is associated with decreased survival of patients, thus suggesting its utility as a prognostic biomarker for patients diagnosed with high-grade astrocytoma (Drucker et al., 2015).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
12725415	2003	The prognostic value of the human kallikrein gene 9 (KLK9) in breast cancer.	Yousef GM et al
17573418	2007	Distribution of 15 human kallikreins in tissues and biological fluids.	Shaw JL et al
26231762	2015	Prognostic significance of multiple kallikreins in high-grade astrocytoma.	Drucker KL et al
94166	1979	Kallikreins (kininogenases)--a group of serine proteases with bioregulatory actions.	Schachter M et al

Other Information

Locus ID:

NCBI: 284366
MIM: 605504
HGNC: 6370
Ensembl: ENSG00000213022

Variants:

dbSNP: 284366
ClinVar: 284366
TCGA: ENSG00000213022
COSMIC: KLK9

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000213022	ENST00000544410	Q9UKQ9
ENSG00000213022	ENST00000594211	Q9UKQ9
ENSG00000213022	ENST00000594211	Q2XQG6

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
28559305	2017	Biochemical and functional characterization of the human tissue kallikrein 9.	1
29095848	2017	Clinical relevance of kallikrein-related peptidase 9, 10, 11, and 15 mRNA expression in advanced high-grade serous ovarian cancer.	12
28559305	2017	Biochemical and functional characterization of the human tissue kallikrein 9.	1
29095848	2017	Clinical relevance of kallikrein-related peptidase 9, 10, 11, and 15 mRNA expression in advanced high-grade serous ovarian cancer.	12
25747782	2015	Human tissue kallikrein 9 in asthmatic patients.	1
26231762	2015	Prognostic significance of multiple kallikreins in high-grade astrocytoma.	14
25747782	2015	Human tissue kallikrein 9 in asthmatic patients.	1
26231762	2015	Prognostic significance of multiple kallikreins in high-grade astrocytoma.	14
20424135	2010	Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer.	37
20424135	2010	Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer.	37

Citation

Panagiotis G. Adamopoulos ; Andreas Scorilas

KLK9 (kallikrein-related peptidase 9)

Atlas Genet Cytogenet Oncol Haematol. 2016-09-01

Online version: http://atlasgeneticsoncology.org/gene/47324