Extracellular Phosphorylation and Phosphorylated Proteins: Not Just Curiosities But Physiologically Important

Abstract

Mining of the literature and high-throughput mass spectrometry data from both healthy and diseased tissues and from body fluids reveals evidence that various extracellular proteins can exist in phosphorylated states. Extracellular kinases and phosphatases (ectokinases and ectophosphatases) are active in extracellular spaces during times of sufficiently high concentrations of adenosine triphosphate. There is evidence for a role of extracellular phosphorylation in various physiological functions, including blood coagulation, immune cell activation, and the formation of neuronal networks. Ectokinase activity is increased in some diseases, including cancer, Alzheimer's disease, and some microbial infections. We summarize the literature supporting the physiological and pathological roles of extracellularly localized protein kinases, protein phosphatases, and phosphorylated proteins and provide an analysis of the available mass spectrometry data to annotate potential extracellular phosphorylated proteins.

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

“…Hsin-Wei Liao, 1,2 Jung-Mao Hsu, 1 Weiya Xia, 1 Hung-Ling Wang, 3 Ying-Nai Wang, 1,3,4 Wei-Chao Chang, 3 Stefan T. Arold, 5,6 Chao-Kai Chou, 1,3 Pei-Hsiang Tsou, 1 Hirohito Yamaguchi, 1 Yueh-Fu Fang, 1,7 Hong-Jen Lee, 1,2 Heng-Huan Lee, 1 Shyh-Kuan Tai, 8 Mhu-Hwa Yang, 9 Maria P. Morelli, 10 Malabika Sen, 11 John E. Ladbury, 5,12 Chung-Hsuan Chen, 13 Jennifer R. Grandis, 11,14 Scott Kopetz, 10 and Mien-Chie Hung ing activation of HER2 or MET signaling, mutation of PIK3CA and BRAF, or expression status of PTEN, but retrospective analyses revealed inconsistent and controversial findings (16). So far, the most accepted predictive marker for poor cetuximab response is mutant KRAS status, due to its association with poor survival rate under cetuximab treatment in colorectal cancer clinical trials (17)(18)(19)(20).…”

“…There is evidence that extracellular modifications of transmembrane proteins have important physiological functions. For example, extracellular domain phosphorylation of cadherin protein by intracellular Golgi kinase or ectokinase regulates cell adhesion, cell growth, and cell polarity (6,7). In addition, glycosylation on the extracellular domain of RTK is critical for protein stabilization and subcellular localization (5,8).…”

Phosphorylation of substrates destined for secretion by the Fam20 kinases

“…In the extracellular space, numerous phosphoproteins are present, and multisite phosphorylation appears to be a common theme [2][3][4][5]. For example, milk caseins are highly phosphorylated proteins and are used in protein kinase research as model substrates to detect acidophilic protein kinase activity [6].…”

Ecto-protein kinases and phosphatases: an emerging field for translational medicine

“…All preconditions for protein kinases to be active also exist in the extracellular environment, such as sufficiently high concentrations of extracellular ATP and a growing body of evidence is documenting the existence and activity of these enzymes in extracellular spaces (Figure 1; [4-7]). In fact, evidence that many prominent kinases and phosphatases are located extracellularly has been obtained in-vivo as well as in-vitro including FAM20C [7], PKA [8,9], PKC [10,11], CKII [12], alkaline phosphatase [13], tartrate-resistant acid phosphatase (TRAP) [14] and the PTEN phosphatase [15] (Table 1).…”