Ectokinases as novel cancer markers and drug targets in cancer therapy

Abstract

While small-molecule kinase inhibitors became the most prominent anticancer drugs, novel combinatorial strategies need to be developed as the fight against cancer is not yet won. We review emerging literature showing that the release of several ectokinases is significantly upregulated in body fluids from cancer patients and that they leave behind their unique signatures on extracellular matrix (ECM) proteins. Our analysis of proteomic data reveals that fibronectin is heavily phosphorylated in cancer tissues particularly within its growth factor binding sites and on domains that regulate fibrillogenesis. We are thus making the case that cancer is not only a disease of cells but also of the ECM. Targeting extracellular kinases or the extracellular signatures they leave behind might thus create novel opportunities in cancer diagnosis as well as new avenues to interfere with cancer progression and malignancy.

Concepts of extracellular matrix remodelling in tumour progression and metastasis

“… αvβ3 and αvβ6 integrins Glycosyltransferases and glycosidases Breast cancer Inhibition of glycosylation increases the invasion properties of metastatic cells 265 . Phosphorylation Fibronectin Casein kinase II-like protein kinase Many types 266 Phosphorylated fibronectin increases mechanical cell functions and cell traction forces for attachment 266 and occurs at growth factor binding sites 267 . Many targets including MMPs and laminin A1 Vertebrate lonesome kinase (VLK) and extracellular serine/threonine protein kinase (FAM20C) Currently poorly understood 268 Extracellular kinases phosphorylate ECM and ECM-associated components, which can potentially alter downstream kinase signalling pathways 268 , 269 .…”

Proteomic database mining opens up avenues utilizing extracellular protein phosphorylation for novel therapeutic applications

“…Most recently, protein kinases such as VLK and FAM20C (also known as Golgi casein kinase), have been shown to be secreted through the classical ER-Golgi secretory pathway [ 1 , 2 ]. In addition, several protein kinases and phosphatases, including PKA [ 3 , 4 ], PKC [ 5 , 6 ], CKII [ 7 ], alkaline phosphatase [ 8 ], tartrate-resistant acid phosphatase (TRAP) [ 9 ] and the PTEN phosphatase [ 10 ], have been shown to accumulate in conditioned cell culture media of different cell lines [ 11 ], as well as in human plasma and/or serum samples from cancer patients [ 12 ]. Furthermore, these kinases have been shown to be functional in conditioned serum-free cell culture media [ 13 ] and/or sera [ 14 ].…”

Vertebrate Lonesome Kinase Regulated Extracellular Matrix Protein Phosphorylation, Cell Shape, and Adhesion in Trabecular Meshwork Cells

“…Based on the VLK data from our studies, it is conceivable that Fam20C might also play a role in the AH outflow pathway. Fam20C is another well characterized ectokinase which regulates serine phosphorylation of various ECM and other extracellular proteins, and has been shown to play a crucial role(s) in both physiological and pathological processes (Tagliabracci et al, ; Yalak and Vogel, ; Tagliabracci et al, ; Cui et al, ; Tagliabracci et al, ; Yalak and Vogel, ). TM cells are confirmed to express Fam20A, 20B, and 20C based on RT‐PCR analyses (our unpublished data) which coordinately regulate serine phosphorylation of different extracellular proteins (Cui et al, ).…”

“…Secretory kinase‐mediated phosphorylation of ECM proteins, MMPs, and several other secretory proteins occurs on serine, threonine, and tyrosine residues, and utilizes extracellular ATP resulting either from cell death or through other mechanisms (Yalak and Vogel, ; Tagliabracci et al, ; Bordoli et al, ; Tagliabracci et al, ). The secretory kinases vertebrate lonesome kinase (VLK) and Fam20C, which phosphorylate various secretory proteins including the ECM proteins and MMPs, are thought to be relevant in both physiological and pathological conditions (Simpson et al, ; Kinoshita et al, ; Bordoli et al, ; Tagliabracci et al, ; Yalak and Vogel, ). VLK, a secretory tyrosine kinase (also known as protein kinase domain containing protein, cytoplasmic‐PKDCC and sgk493), has also been shown to regulate protein transport through the Golgi and endoplasmic reticulum, and formation of stroma and differentiation of chondrocytes (Imuta et al, ; Kinoshita et al, ; Bordoli et al, ).…”