Richard Anderson Lab

Research: Cell Migration, Invasion and Metastasis

Signaling pathways that regulate cell morphogenesis, cell polarity, proliferation, cell migration/invasion, receptor trafficking and cancer progression

We focus on mechanisms by which cells regulate polarity with an emphasis on cytoskeletal dynamics and the trafficking of adhesion and growth factor receptors. These processes regulate the dynamics of cell-cell contacts assembly during epithelial morphorgenesis and cell to matrix adhesion during migration/invasion (Nature, 420:89-93, Dev. Cell, 22, 116–130). These combined events are the underpinnings of cancer metastasis. These projects have a translational emphasis on cancer progression and metastasis but are also fundamental in cardiovascular diseases and many biological processes. A current emphasis is the type Ig PIP kinase (PIPKIγ) family of enzymes that are generated by pre-mRNA splicing(Biochem. J. 422, 473-482). PIPKIγi1-7 family members are differentially targeted in cells and have distinct cellular functions.

Figure 1

Figure 1. PIPKIγi2 regulated polarized trafficking of adhesion receptors controls directional cell migration (Dev. Cell, 22, 116–130).

The role of cytoskeletal dynamics in cell migration and invasion

PI4,5P2 modulates actin assembly and dynamics at the leading edge of migratory cells, although the mechanisms are poorly defined. Recently, we have shown that the IQGAP1-3 proteins interact with PIP kinases and are PI4,5P2 effectors (EMBO J. 32, 2617-30). The IQGAP proteins are signaling scaffolds that interact with multiple G-proteins, protein kinases, adhesion receptors and other signaling molecules. Type Iα and Iγ PIP kinase isoforms bind IQGAP1-3 and both PIP kinases and IQGAPs have roles in cancer progression. The interaction of PIPKIg isoforms regulate IQGAP1’s role in directional cell migration/invasion and cell polarization, whereas type Ia PIP kinase (PIPKIα) modulate receptor activation of PI 3-kinase pathways. IQGAP binding of PIPKs, and modulation by PI4,5P2 and other PIPn isomers occurs at multiple sites and regulates the assembly of multiple signaling IQGAP complexes (EMBO J. 32, 2617-30). These complexes regulate the diversity of roles controlled by IQGAP1-3, PIP kinases and PIPn isomers. Defining these mechanisms and functional roles for PIP kinase modulation of IQGAP1-3 will contribute to understanding the morphogenesis of cell polarity, cell migration/invasion and proliferation, key underpinnings for metastasis, wound healing and development. The IQGAP1-3 isoforms have distinct cellular functions and we are exploring how the different PIPKs regulate different IQGAP biological functions and integrate the IQGAPs and PIPKs into specific pathways.

Polarized membrane trafficking

The PIPKI isoforms regulate membrane trafficking and secretion (Nature 374, 173-177). Recently, we have defined a role for the PIPKIγi2 isoform and the exocyst in directional membrane trafficking that controls b-integrin (and other receptors) targeting to talin rich adhesion complexes at the leading edge of migrating cells (Dev. Cell, 22, 116–130). In this pathway (Fig. 1), PIPKIγi2 directly interact with both the exocyst and talin linking these two protein and delivers b-integrin containing vesicle to plasma membrane regions rich in talin (adhesion complexes). The generation of PI4,5P2 modulates both exocyst and also the talin interaction with b-integrins which controls focal adhesion assembly and cell-matrix interactions, key events in migration and invasion. This pathway also modulates trafficking of membrane receptors that control epithelial polarization (Mol. Biol. Cell. 23, 87-98). Currently, we are identifying specific receptors/membrane proteins trafficked by this pathway, the mechanisms for receptor specificity, and the role of this pathway in the metastasis of breast cancer cells using mouse models.

Microenvironment regulation of cell growth

Emerging results indicate that PIP kinase family members integrate into multiple growth regulatory pathways that are dependent upon environmental cues. For example, the PIPKIγi2 isoform integrates into a signaling nexus with Src and PI 3-kinase that is required for anchorage independent cell growth(JBC 288, 34707–34718) and the development of mammospheres with breast cancer stem cell phenotypes. Yet growth of these same cells in 2-D is independent of PIPKIγi2 but in this environment requires PIPKIα. Consistently, PIPKIγ isoforms are required for the metastasis of breast cancer cells and over expression (or loss of specific isoforms), as observed in triple negative breast cancers, enhances metastasis of breast cancer cells in a mouse model.