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Review
. 2019 May 30;20(11):2653.
doi: 10.3390/ijms20112653.

The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals

Rokib Hasan  1 , Guo-Lei Zhou  2   3
Affiliations
Review

The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals

Rokib Hasan et al. Int J Mol Sci. .

Abstract

As a conserved actin-regulating protein, CAP (adenylyl Cyclase-Associated Protein) functions to facilitate the rearrangement of the actin cytoskeleton. The ubiquitously expressed isoform CAP1 drives mammalian cell migration, and accordingly, most studies on the involvement of CAP1 in human cancers have largely been based on the rationale that up-regulated CAP1 will stimulate cancer cell migration and invasiveness. While findings from some studies reported so far support this case, lines of evidence largely from our recent studies point to a more complex and profound role for CAP1 in the invasiveness of cancer cells, where the potential activation of cell adhesion signaling is believed to play a key role. Moreover, CAP1 was also found to control proliferation in breast cancer cells, through the regulation of ERK (External signal-Regulated Kinase). Alterations in the activities of FAK (Focal Adhesion Kinase) and ERK from CAP1 depletion that are consistent to the opposite adhesion and proliferation phenotypes were detected in the metastatic and non-metastatic breast cancer cells. In this review, we begin with the overview of the literature on CAP, by highlighting the molecular functions of mammalian CAP1 in regulating the actin cytoskeleton and cell adhesion. We will next discuss the role of the FAK/ERK axis, and possibly Rap1, in mediating CAP1 signals to control breast cancer cell adhesion, invasiveness, and proliferation, largely based on our latest findings. Finally, we will discuss the relevance of these novel mechanistic insights to ultimately realizing the translational potential of CAP1 in targeted therapeutics for breast cancer.

Keywords: CAP1; ERK; FAK; breast cancer; cell adhesion; cell invasiveness; cell proliferation; the actin cytoskeleton.

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Conflict of interest statement

The authors declare no conflict of interest. The funding sponsor had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
The structural organization of CAP1. CAP1 can be divided into three domains that are conserved across CAP homologues from species. Highlighted are the functions that are mediated by separate domains that are relevant to cell migration, largely for those important in facilitating actin dynamics. The C-terminus also binds Rap1, which can may mediate CAP1 functions in cell adhesion and proliferation. CAP1 also associates with FAK/talin to regulate those cell functions; however, the domain on CAP1 responsible for this interaction has yet to be determined, and are thus not shown here.
Figure 2
Figure 2
Inhibition of FAK activity, but not the depletion of c-Abl, reduced ERK activity in MDA-MB-231 cells, suggesting that FAK mediates CAP1 signals to regulate ERK. (A) The control and CAP1-knockdown MDA-MB-231 metastatic breast cancer cells were treated with 5 μg/mL FAK inhibitor PF-573228 (SelleckChem) for 13 h before cells were harvested for Western blotting, to detect the effects on ERK activity. Antibodies against FAK, pFAK(Tyr397), ERK, and pERK (Thr202/Tyr204) were from Cell Signaling Technology Inc., and that against GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase) was from Santa Cruz Biotechnology Inc. The control indicates the stable cells that harbor the empty vector of the CAP1 knockdown shRNA construct, and CAP1KD indicates CAP1-knockdown-stable cells that we previously established. (B) Transient silencing of c-Abl with the siRNA (SCBT #sc-29310) in the control and CAP1-knockdown MDA-MB-231 cells did not have a remarkable effect on ERK activity. The antibody against c-Abl was from Cell Signaling Technology Inc. Cells were cultured for 24 h in DMEM supplemented with 10% fetal bovine serum and then transfected with the siRNA, following the manufacturer’s protocol. Cells were harvested 48 h after transfection for analyses in Western blotting, to confirm the depletion of c-Abl and its effects on ERK activity.
Figure 3
Figure 3
A schematic model depicting how CAP1 likely regulates the FAK/ERK axis and Rap1, and through these, controls invasiveness and proliferation in metastatic breast cancer cells. Knockdown of CAP1 activates FAK, and which in turn activates ERK. The activated ERK and Rap1 lead to elevated cell proliferation. On the other hand, enhanced cell adhesion and increased turnover of focal adhesions from activated FAK and Rap1, as well as the activated ERK/Snail/E-Cadherin signals may collectively stimulate cancer cell invasiveness, and overcome negative effects on cancer cell invasiveness from the reduced rate of actin filament turnover, due to the loss of CAP1 function in these cells. The cell signals that function in cohort to control transient phosphorylation at the S307/S309 tandem regulatory site on CAP1 likely control the cancer cell functions through CAP1.
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