Receptor Kinases & Phosphatases

TGF-beta Program

Transforming growth factor (TGF) -β is the archetypal member of a super-family of cytokines that regulate cell growth, differentiation, proliferation and apoptosis (programmed cell death), and also tumor invasiveness. By binding to type I (ALK) and type II receptors, TGF-β members trigger a complicated signal transduction system involving the selective activation and inhibition of intracellular proteins known as ‘Smads’, ultimately resulting in gene transcription by Smad protein complexes.

Smad7 Levels Predict Prostate Cancer Therapy Response

The TGF-β type I receptor family, ALK1-6, were discovered and characterized by investigators from the Uppsala Branch in the early 1990’s. These results formed the basis of LICR’s TGF-β Program, which integrates research from the Uppsala, Brussels and Melbourne Branches and Affiliate investigators in the Netherlands and Japan.

The compound 2-methoxyestradiol (2-ME) is being investigated as a potential cancer therapy because of its capacity to inhibit tumor angiogenesis and cause cancer cell apoptosis. LICR investigators from the Uppsala Branch showed that the apoptotic effect of 2-ME is dependent upon the gene expression of Smad7, a TGF-β signaling pathway adaptor molecule, in prostate cancer cells(1,2). These findings suggest that measuring Smad7 levels in prostate cancer patients may indicate which patients will or will not benefit from treatment with 2-ME. The team also delineated the signaling pathways in TGF-β-induced apoptosis of prostate cancer cells, identifying crucial roles for Smad7 and β-catenin, a signaling protein mutated in many cancers.

New TGF-β/Cytokine Link in Gastric Cancer

TGF-β/Smad and cytokine/STAT are two powerful signaling pathways that have been implicated independently in cancer onset and progression. Investigators from the Melbourne Branch have now established a novel link between these two pathways in the initiation and progression of tumor formation in the stomach(3). In the mouse, excessive activation of STAT3 induces the TGF-β inhibitor protein, Smad7, which causes epithelial cells to be released from TGF-β’s cell cycle control. Importantly, gene expression profiles from human tumor samples suggest the same mechanism is occurring in human gastric cancer. These results add further weight to the argument for developing cancer therapies that target STAT3 and TGF-β.

TGF-β/Smad3 Counteracts BRCA-1 in Breast Cancer

Mutations in the BRCA-1 gene, which regulates DNA damage repair, gene transcription and chromatin remodeling, confer susceptibility to early-onset familial breast and ovarian cancers. A team from the Uppsala Branch has shown that Smad3 binds to BRCA1 and suppresses BRCA1-dependent DNA repair in breast cancer cells(4). The team also conducted the first phosphoproteomic analysis of TGF-β stimulated cells and learned more about TGF-β-induced gene expression in breast cancer cells(5). A phosphoproteomic analysis detects proteins activated by ‘phosphorylation’, the addition of a phosphate group. At left is an image of proteins (appearing as black spots on a silver background) phosphorylated in response to TGF-β stimulation of breast cancer cells.

References

  1. Edlund S, Lee SY, Grimsby S, Zhang S, Aspenstrom P, Heldin CH, Landstrom M. Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Molecular Cell Biology (2005) 25(4):1475-88.
  2. Davoodpour P, Landstrom M. 2-Methoxyestradiol-induced apoptosis in prostate cancer cells requires Smad7. Journal of Biological Chemistry (2005) 280(15):14773-9.
  3. Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu HJ, Ernst M. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nature Medicine (2005) 11(8):845-52.
  4. Dubrovska A, Kanamoto T, Lomnytska M, Heldin CH, Volodko N, Souchelnytskyi S. TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage. Oncogene (2005) 24(14):2289-97.
  5. Stasyk T, Dubrovska A, Lomnytska M, Yakymovych I, Wernstedt C, Heldin CH, Hellman U, Souchelnytskyi S. Phosphoproteome profiling of transforming growth factor (TGF)-beta signaling: abrogation of TGFbeta1-dependent phosphorylation of transcription factor-II-I (TFII-I) enhances cooperation of TFII-I and Smad3 in transcription. Molecular Biology of the Cell (2005) 16(10):4765-80.

Centers Involved in this Research