Target Analysis of Human SYK

Human SYK

Spleen tyrosine kinase (SYK) is a cytosolic non-receptor tyrosine kinase mainly presiding over the inflammatory process. It is a multidomain protein that has two tandem SH2 domains and a kinase domain followed by a short C-terminal tail. SYK is expressed in all cells of the hematopoietic cell lineage and also in non-hematopoietic cells such as epithelial cells, fibroblasts, and neuronal and vascular endothelial cells. This tyrosine kinase is a key mediator of immune receptor-signaling in host inflammatory cells (B cells, mast cells, macrophages and neutrophils), important for both allergic and antibody-mediated autoimmune diseases. De-regulated SYK kinase activity also allows growth factor-independent proliferation and transforms bone marrow-derived pre-B cells that are able to induce leukemia. Consequently, the development of SYK kinase inhibitors could possibly treat these disorders and so it has attracted considerable interest as a therapeutic target.

SYK inhibition blocks three mast cell functions: the release of mediators such as histamine, the production of prostaglandins and leukotrienes, and the secretion of cytokines. Even more important is the capability of SYK kinase inhibitors to inhibit the expression of key factors induced by inflammatory response, avoiding the side effects of systemic antihistamine treatment. Furthermore, in hematologic malignancies SYK inhibition blocks cell proliferation and induces apoptosis leading to tumor regression. Conversely, SYK inhibitors are not likely to cause a significant impact on the growth of platelets and other non-hematopoietic cells because a multitude of SYK-independent mechanisms regulates their activity. For these reasons, SYK inhibitors are emerging as promising therapeutic agents for managing inflammatory diseases like allergic and antibody-mediated autoimmune diseases as well as for the treatment of lymphoma.

The fact that SYK inhibitors have the capacity to ameliorate allergic and autoimmune diseases and also several common B-cell malignancies has influenced their strategic development. In this report, we analyze the SYK gene with respect to its pharamacogenomic properties. The areas of focus include:

• Gene summary
• Orthologs and paralogs
• Alternate transcription
• Expression
• SNP analysis
• Other genetic alterations
• Promoter analysis
• Protein domains
• Disease

Table of Contents

1. Gene Summary - 4

2. Orthologs of SYK - 5

3. Alternative transcription of SYK - 10
  3A. Alternative transcripts in humans - 10
  3B. SYK expression in normal tissues - 13
  3C. Alternate transcripts of SYK in mammalian model organisms - 15

4. Polymorphisms in SYK - 15
  4A. SYK polymorphisms in humans - 16
  4B. Coding region polymorphisms- location and type - 18
  4C. Discussion of coding region polymorphisms - 19  
  4D. Non-Coding region polymorphisms - location and risk - 23  
  4E. Population allele frequencies of SYK polymorphisms with moderate or high risk - 26  
  4F. SYK polymorphisms in humans - reported in literature - 28  
  4G. Syk polymorphisms in mouse - 30

5. Other genetic alterations - 31
  5A. Mutations - 31
  5B. Methylation and acetylation - 32
  5C. Chromosomal aberrations - 34
  5D. miRNA targets in the SYK gene - 37

6. Promoter analysis - 38

7.Paralogs - 39

8. Protein family and domain - 43

9. Expression and activity of SYK in disease - 49
  9A. SYK and cancer - 52
  9B. SYK and non-neoplastic diseases - 59

References - 65

COPYRIGHT INFORMATION - 73

Executive Summaries and Sample Pages |  Sample Appendix