Pat Caswell, MSc PhD
Integrin trafficking

Integrins and signalling receptors are cell surface proteins which enable the cell to interpret its physical and chemical environment.  Together these cell surface proteins dictate the fate of the cell: whether to grow, move to new surroundings, differentiate into a specialised cell or die.  Failure to respond correctly to the surrounding environment can promote the initiation and progression of diseases such as cancer.  We aim to elucidate the mechanisms through which cells interpret and respond accordingly to their surroundings, and determine how these mechanisms are co-opted in cancer.

The tip of an invasive pseudopod, with an actin polymerizing protein (green) decorating the ends of actin filaments (red).

Integrins and signalling receptors reside at the surface of the cell, and inside the cell within specialised compartments called endosomes.  Integrins are exchanged between endosomes and the cell surface, and this ‘trafficking’ of integrins alters the way in which signalling receptors transmit the messages that allow the cell to interpret new surroundings.  Our laboratory investigates the way in which movement of integrins between endosomes and the cell surface controls signalling pathways within the cell that determine the appropriate response to the surrounding environment in order to understand how cancer cells manipulate integrin trafficking pathways in order to escape the primary tumour and disseminate to form metastases, and how integrin trafficking influences the ability of cells to differentiate.

The scientific story

PA-GFPIntegrins are an important family of cell surface receptors for extracellular matrices, which act in concert with many signalling receptors, and our research addresses the mechanisms that underlie integrin-mediated coordination of signals from the extracellular matrix (ECM) and soluble growth factors and cytokines in cells as they migrate and differentiate. Endocytic trafficking is becoming recognised as an important regulator of intracellular signalling events, and it is now clear that integrin trafficking pathways influence the trafficking of growth-factor receptors and their downstream signaling. We use a variety of cell biology and biochemistry techniques, with particular focus on live-cell imaging and photoactivatable fluorescent proteins, in 3D-model systems that more closely mimic the physiological environment found in vivo to investigate two major areas:

The tip of an invasive pseudopod, with an actin polymerizing protein (green) decorating the ends of actin filaments (red).

1. Integrin-mediated trafficking and signaling in cancer cell invasion

Alpha-5 beta-1 integrin trafficking, which can be promoted by expression of gain-of-function mutant p53, expression of Rab25, or by inhibition of alpha-v beta-3, promotes invasive migration of tumour cells within

fibronectin containing 3D-microenvironments. Enhanced trafficking of alpha-5 beta-1 has little influence on activation status of the integrin, or the ability of integrin to mediate attachment to fibronectin ligands. Rather, integrin trafficking controls the recycling of EGFR1, potentiating EGFR1 activation and modulating downstream signalling to favour to PKB/Akt.

We are characterising the complexes formed by alpha-5 beta-1 in invasive cancer cells using quantitative mass spectrometry, allowing us to identify the molecular players which potentiate and modulate EGFR signalling and thus are pivotal to the pro-metastatic programme of carcinoma.

2. Integrin trafficking in differentiating epithelial cells

Integrin-mediated trafficking of growth-factor receptors promotes tumour angiogenesis and invasive migration of cancer cells. The molecular machinery which controls such trafficking and signalling in cancer is likely to have been co-opted from developmental/differentiation processes, however the role of integrin-mediated trafficking and signalling in regulating normal physiological function is unclear. We are investigating integrin trafficking, and its role in the regulation of intracellular signalling pathways, during the differentiation of mammary epithelial cells, with particular focus on prolactin receptor signalling.  We are further trying to understand how the pathways that function in normal physiology are hijacked during the initiation and progression of cancer.

Recent key publications

Jacquemet, G., Green, D.M., Bridgewater, R.M., von Kriegsheim, A., Humphries, M.J.,  Norman, J.C. and Caswell, P.T. (2013). RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex. J Cell Biol. in press. Epub 

Dozynkiewicz, M.A.,  Jamieson, N.B., MacPherson, I., Grindlay, J., van den Berghe, P., von Thun, A., Morton, J.P., Gourley, C., Timpson, P., Nixon, C., McKay, C.J., Carter, R., Strachan, Anderson, K.,  Sansom, O.J.,  Caswell, P.T., Norman, J.C. (2012). Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev Cell. 22, 131-45. PubMed

Rainero, E., Caswell, P.T., Muller, P.A., Grindlay, J., McCaffrey, M.W., Zhang, Q., Wakelam, M.J., Vousden, K.H., Graziani, A., Norman, J.C. (2012). Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol. 196, 277-95. PubMed

Full list of publications