Cell Signaling and Regulatory Networks

CellSignaling280-220Osteoblasts and hematopoietic cells respond to a variety of extracellular signals. Fidelity of signaling responses is essential for biological outcomes in both lineages. Our laboratory has identified many cell signaling pathways that culminate at Runx target gene promoters, enhancers, and upstream regulatory elements. These include TGFβ/BMP2, Wnt, and Src tyrosine kinase signaling pathways in osteoblasts and the MAPK pathway in hematopoiesis that support protein/protein interactions of Runx proteins with critical co-factors. We discovered that these pathways are integrated by Runx proteins at target gene loci associated with distinct nuclear microenvironments (see Nuclear Structure and Function). Integration of signaling pathways at subnuclear sites of transcription provides a mechanistic model for regulatory communication from the extracellular milieu via the cell surface to the nucleus where gene regulation occurs. Using CRISPR-modified human cells in a xenograft model, we are now delineating the in vivo roles of these pathways linked to higher-order chromatin organization and the subnuclear functions of Runx proteins during the epithelial to mesenchymal transition associated with breast cancer tumorigenesis as well as for bone cell development and fracture repair.

Landmark Papers

  • Teplyuk NM, Galindo M, Teplyuk VI, Pratap J, Young DW, Lapointe D, Javed A, Stein JL, Lian JB, Stein GS, van Wijnen AJ. Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors. J Biol Chem. 2008 Oct 10;283(41):27585-97.

  • Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, Hussain S, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res. 2008 Oct 1;68(19):7795-802.

  • Lengner CJ, Steinman HA, Gagnon J, Smith TW, Henderson JE, Kream BE, Stein GS, Lian JB, Jones SN. Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J Cell Biol. 2006 Mar 13;172(6):909-21.

  • Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS, Javed A, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem. 2005 Sep 30;280(39):33132-40.

  • Zaidi SK, Sullivan AJ, Medina R, Ito Y, van Wijnen AJ, Stein JL, Lian JB, Stein GS. Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J. 2004 Feb 25;23(4):790-9.

  • Zaidi SK, Sullivan AJ, van Wijnen AJ, Stein JL, Stein GS, Lian JB. Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8048-53.

  • Aslam F, McCabe L, Frenkel B, van Wijnen AJ, Stein GS, Lian JB, Stein JL. AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation. Endocrinology. 1999 Jan;140(1):63-70.