Cell Migration and Invasion

The mechanisms of tumor cell adhesion, motility and invasion are extremely complex and essential components of the metastatic process. Dr. McNiven's lab was the first to show an interaction between dynamin and a component of the actin cytoskeleton, cortactin, which is an actin-binding, src-substrate protein. The concept of an src-substrate, actin-remodeling protein binding to a mechoenzyme such as dynamin is attractive. Further, these proteins colocalize in the leading lamellipodia of migrating tumor cells and appear to be essential in cytoskeletal reorganization to facilitate migration. How these proteins interact to regulate cytoskeletal and membrane dynamics during tumor cell migration is a central focus of the lab.

  • EGFR Recycling Is Mediated by a Novel Form of Eps15

  • Dyn2 potentiates metastatic migration and invasion of pancreatic ductal carcinoma

  • Dyn2 and FAK regulates focal adhesion dynamics

  • Dyn2 binds γ-tubulin and participates in centrosome cohesion

  • Invasive matrix degradation at focal adhesions by a FAK-p130Cas complex

  • Phospho-forms of cortactin regulate actin polymerization and focal adhesions

View the publications below to learn more about the lab's work.

Increased expression of the large GTPase dynamin 2 potentiates metastatic migration and invasion of pancreatic ductal carcinoma

Oncogene. 2012 Mar; 31(10):1228-41. doi: 10.1038/onc.2011.329.

Robbin D. Eppinga, Eugene W. Krueger, Shaun G. Weller, Lizhi Zhang, Hong Cao, Mark A. McNiven

Src-mediated tyrosine kinase signaling pathways promote pancreatic ductal adenocarcinoma (PDAC) metastasis, though the molecular mechanisms supporting this invasive process are poorly understood and represent important and novel therapeutic targets.

The goal of this study was to test if large GTPase dynamin 2 (Dyn2), an src-kinase substrate, is upregulated in human pancreatic tumors and to define its role in cell migration and metastatic invasion using in vitro assays and nude mouse models. Findings are the first to implicate dynamin in any neoplastic condition and to directly demonstrate a role for this mechanoenzyme in invasive cell migration.

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Invasive matrix degradation at focal adhesions occurs via protease recruitment by a FAK-p130Cas complex

Journal of Cell Biology. 2012;196(3):375.

Yu Wang, Mark A. McNiven

Tumor cell migration and the concomitant degradation of extracellular matrix (ECM) are two essential steps in the metastatic process. It is well established that focal adhesions (FAs) play an important role in regulating migration; however, whether these structures contribute to matrix degradation is not clear. In this study, we report that multiple cancer cell lines display degradation of ECM at FA sites that requires the targeted action of MT1-MMP. These findings demonstrate a novel function for FAs and also provide molecular insights into MT1-MMP targeting and function.

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A direct interaction between the large GTPase dynamin-2 and FAK regulates focal adhesion dynamics in response to active src

Molecular Biology of the Cell. 2011; 22(9):1529.

Yu Wang, Hong Cao, Jing Chen, Mark A. McNiven

Tumor cell migration is supported in part by the cyclic formation and disassembly of focal adhesions (FAs); however, the mechanisms that regulate this process are not fully understood. This study defines a novel mechanism of how Dyn2 functions as a downstream effector of FAK-Src signaling in turning over FAs.

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Distinct phospho-forms of cortactin differentially regulate actin polymerization and focal adhesions

Cell Physiology: American Journal of Physiology. 2008; 295(5):C1113.

Anne E. Kruchten, Eugene W. Krueger, Yu Wang, Mark A. McNiven.

Cortactin is an actin-binding protein that is overexpressed in many cancers and is a substrate for both tyrosine and serine/threonine kinases. Findings provide novel insights into how distinct phospho-forms of cortactin may differentially contribute to actin and focal adhesion dynamics to control cell migration.

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Dynamin 2 binds γ-tubulin and participates in centrosome cohesion

Dynamin 2 binds γ-tubulin and participates in centrosome cohesion

Nature Cell Biology. 2004; 6(4):335.

Heather M. Thompson, Hong Cao, Jing Chen, Ursula Euteneuer, Mark A. McNiven

Dynamin 2 (Dyn2) is a large GTPase involved in vesicle formation and actin reorganization1-3. In this study, we report a novel role for Dyn2 as a component of the centrosome that is involved in centrosome cohesion. These findings suggest a novel function for Dyn2 as a participant in centrosome cohesion.

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A dynamin-cortactin-arp2/3 complex mediates actin reorganization in growth factor-stimulated cells

Molecular Biology of the Cell. 2003 March; 14:1085-1096.

Eugene W. Krueger, James D. Orth, Hong Cao, Mark A. McNiven

The mechanisms by which mammalian cells remodel the actin cytoskeleton in response to motogenic stimuli are complex and a topic of intense study. Dynamin 2 (Dyn2) is a large GTPase that interacts directly with several actin-binding proteins, including cortactin. Findings demonstrate that cortactin and Dyn2 function together in a supramolecular complex that assembles in response to growth factor stimulation and mediates the remodeling of actin to facilitate lamellipodial protrusion at the leading edge of migrating cells.

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The large GTPase dynamin regulates actin comet formation and movement in living cells

The large GTPase dynamin regulates actin comet formation and movement in living cells

PNAS. 2001;99(1):167.

James D. Orth, Eugene W. Krueger, Hong Cao, Mark A. McNiven.

The large GTPase dynamin (Dyn2) has been demonstrated by us and others to interact with several different actin-binding proteins. To define how Dyn2 might participate in actin dynamics in livings cells, we have expressed green fluorescent protein (GFP)-tagged Dyn2 in cultured cells and observed labeling of comet-like vesicles and macropinosomes. These findings demonstrate a role for Dyn2 in actin-based vesicle motility.

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Regulated interactions between dynamin and the actin-binding protein cortactin modulate cell shape

Regulated interactions between dynamin and the actin-binding protein cortactin modulate cell shape

Journal of Cell Biology. 2000;151(1):187.

Mark A. McNiven, Leung Kim, Eugene W. Krueger, James D. Orth, Hong Cao, Tai Wai Wong.

The dynamin family of large GTPases has been implicated in the formation of nascent vesicles in both the endocytic and secretory pathways. It is believed that dynamin interacts with a variety of cellular proteins to constrict membranes. The actin cytoskeleton has also been implicated in altering membrane shape and form during cell migration, endocytosis, and secretion and has been postulated to work synergistically with dynamin and coat proteins in several of these important processes. Findings provide the first demonstration that dynamin can interact with the actin cytoskeleton to regulate actin reorganization and subsequently cell shape.

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