Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.

Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular matrix and various cytokines and growth factors. Fibroblasts are the predominant cell type in the tumor microenvironment. However, neither the derivation of tissue-specific cancer-associated fibroblasts nor markers of tissue-specific cancer-associated fibroblasts are well defined. Despite these uncertainties it is increasingly apparent that cancer-associated fibroblasts have a crucial role in tumor progression. In breast cancer, there is evolving evidence showing that breast cancer-associated fibroblasts are actively involved in breast cancer initiation, proliferation, invasion and metastasis. Breast cancer-associated fibroblasts also play a critical role in metabolic reprogramming of the tumor microenvironment and therapy resistance. This review summarizes the current understanding of breast cancer-associated fibroblasts.

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