Signaling 2003 -
Way Beyond Morse Code

By Peter Emanuel, M.D.

Just think back a little ways ... only 10-15 years ago we were discovering some of the first growth factor receptors on cell surfaces. We thought Ras and only a few other intra-cytoplasmic molecules accounted for most of cellular signaling. Now look where we have progressed to, a plethora of positive and negative signaling regulators, intricately interwoven into a meshwork so complicated even the best signaling experts have difficulties at times. Over the last two days, three different Scientific Committees dealt specifically with signaling events, and today and tomorrow will witness dozens and dozens more abstracts investigating signaling.

In the Scientific Committee on Clinical Laboratory Hematology, Dr. Kuliopulos described the utility of novel cell-penetrating peptides, called pepducins, to act as either inhibitors or agonists for Gprotein coupled receptors. These pepducins thus may serve useful roles in helping to further elucidate signaling pathways, or maybe they will even find their way into the world of therapeutics. Then what will we call them? Dr. Damiano discussed the potential of integrins as novel drug targets to overcome innate drug resistance to imatinib mesylate. Clearly, the more we use imatinib, the more it teaches us that we have a long way to go to cure diseases by interrupting signaling circuits. Dr. Kaushansky delivered a very lucid presentation of the likely role that the c-Mpl/TPO system plays in the development of several chronic myeloproliferative disorders. It appears that, depending on the specific manner of dysregulation of this signaling system, different diseases can be manifested.

In the Scientific Committee on Hematopoietic Growth Factors, negative cell signaling regulators were the focus of discussion. Dr. Krystal discussed his work and the phenotype of SHIP-/- mice. SHIP stands for the hematopoietic-restricted SH2-containing inositol-5’-phosphatase. SHIP should not be confused with SHP-2, the non-receptor tyrosine phosphatase encoded for by the PTPN11 gene, mutations of which have also been recently associated with leukemogenesis. Anyway, SHIP-/- mice suffer from a progressive myeloproliferative disorder because their myeloid progenitors display enhanced survival/proliferation. Dr. Hilton presented his murine models investigating the roles of the Suppressor of Cytokine Signaling- 1 and 3 (SOCS 1 and SOCS 3). SOCS 1 is an important negative regulator of IFNg signal transduction. His SOCS1-/- and SOCS3-/- mouse models suggest that not only can the SOCS proteins regulate quantitative aspects of signaling, they can also influence the quality of the response. Dr. Shannon presented yet another mouse model of dysregulated cytokine signal transduction, that of Nf1-/- mice with dysregulated Ras signal transduction which results in GM-CSF hypersensitivity reproducing what is seen in children with juvenile myelomonocytic leukemia.

In the Scientific Committee on Myeloid Biology, Dr. Coussens presented data from transgenic mouse models investigating the functional significance of matrix metalloproteinases and mast cellderived serine proteases during neoplastic progression. Dr. Clapp discussed the potential role that Ras- Rac hyperactive mast cells via NF1 haploinsufficiency could play in neurofibroma formation. Dr. Cheresh described the coordinated role of integrins and growth factor receptor signaling in angiogenesis. The major growth factors involved in this signaling event are basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF).