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Review
. 2007;48(1):54-72.
doi: 10.1007/s12013-007-0036-3.

Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle

Mahendra Singh  1 , Lauren Cowell, Sachiko Seo, Geraldine O'Neill, Erica Golemis
Affiliations
Review

Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle

Mahendra Singh et al. Cell Biochem Biophys. 2007.

Abstract

Upregulation of the scaffolding protein HEF1, also known as NEDD9 and Cas-L, has recently been identified as a pro-metastatic stimulus in a number of different solid tumors, and has also been strongly associated with pathogenesis of BCR-Abl-dependent tumors. As the evidence mounts for HEF1/NEDD9/Cas-L as a key player in metastatic cancer, it is timely to review the molecular regulation of HEF1/NEDD9/Cas-L. Most of the mortality associated with cancer arises from uncontrolled metastases, thus a better understanding of the properties of proteins specifically associated with promotion of this process may yield insights that improve cancer diagnosis and treatment. In this review, we summarize the extensive literature regarding HEF1/NEDD9/Cas-L expression and function in signaling relevant to cell attachment, migration, invasion, cell cycle, apoptosis, and oncogenic signal transduction. The complex function of HEF1/NEDD9/Cas-L revealed by this analysis leads us to propose a model in which alleviation of cell cycle checkpoints and acquired resistance to apoptosis is permissive for a HEF1/NEDD9/Cas-L-promoted pro-metastatic phenotype.

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Figures

Figure 1
Figure 1. Domain Structure of HEF1/NEDD9/CAS-L
Amino acids encompassing each domain are indicated. See text for details.
Figure 2
Figure 2. Sequence of protein interactions and post-translational modifications “activating” HEF1/NEDD9/CAS-L following integrin ligation
Figure 3
Figure 3. HEF1/NEDD9/CAS-L localization and actions during cell migration
HEF1/NEDD9/CAS-L causes Rac activation in lamellipodia, influencing the dynamics of actin polymerization. HEF1/NEDD9/CAS-L may also contribute to focal adhesion turnover through other protein interactions described in the text.
Figure 4
Figure 4. HEF1/NEDD9/CAS-L in apoptosis/anoikis
Cleavage of HEF1/NEDD9/CAS-L by caspases is inhibited by integrin ligation, and promoted by enforced cell detachment. The carboxy-terminal cleaved fragment of HEF1/NEDD9/CAS-L (p28) actively promotes focal adhesion disassembly and cell death.
Figure 5
Figure 5. HEF1/NEDD9/CAS-L regulation and action through cell cycle
HEF1/NEDD9/CAS-L levels increase through S phase, peaking in G2/M. HEF1/NEDD9/CAS-L relocalizes to centrosomes, and activates Aurora A and RhoA in mitosis.
Figure 6
Figure 6. Model for HEF1/NEDD9/CAS-L in metastasis
See text for details.
See this image and copyright information in PMC

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