TY - JOUR
T1 - Targeting the WASF3 complex to suppress metastasis
AU - Limaye, Ameya J.
AU - Whittaker, Matthew K.
AU - Bendzunas, George N.
AU - Cowell, John K.
AU - Kennedy, Eileen J.
N1 - Funding Information:
This work was supported by the National Institutes of Health [grant number GM134168 to EJK and JKC].
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/8
Y1 - 2022/8
N2 - Wiskott-Aldrich syndrome protein family members (WASF) regulate the dynamics of the actin cytoskeleton, which plays an instrumental role in cancer metastasis and invasion. WASF1/2/3 forms a hetero-pentameric complex with CYFIP1/2, NCKAP1/1 L, Abi1/2/3 and BRK1 called the WASF Regulatory Complex (WRC), which cooperatively regulates actin nucleation by WASF1/2/3. Activation of the WRC enables actin networking and provides the mechanical force required for the formation of lamellipodia and invadopodia. Although the WRC drives cell motility essential for several routine physiological functions, its aberrant deployment is observed in cancer metastasis and invasion. WASF3 expression is correlated with metastatic potential in several cancers and inversely correlates with overall progression-free survival. Therefore, disruption of the WRC may serve as a novel strategy for targeting metastasis. Given the complexity involved in the formation of the WRC which is largely comprised of large protein-protein interfaces, there are currently no inhibitors for WASF3. However, several constrained peptide mimics of the various protein-protein interaction interfaces within the WRC were found to successfully disrupt WASF3-mediated migration and invasion. This review explores the role of the WASF3 WRC in driving metastasis and how it may be selectively targeted for suppression of metastasis.
AB - Wiskott-Aldrich syndrome protein family members (WASF) regulate the dynamics of the actin cytoskeleton, which plays an instrumental role in cancer metastasis and invasion. WASF1/2/3 forms a hetero-pentameric complex with CYFIP1/2, NCKAP1/1 L, Abi1/2/3 and BRK1 called the WASF Regulatory Complex (WRC), which cooperatively regulates actin nucleation by WASF1/2/3. Activation of the WRC enables actin networking and provides the mechanical force required for the formation of lamellipodia and invadopodia. Although the WRC drives cell motility essential for several routine physiological functions, its aberrant deployment is observed in cancer metastasis and invasion. WASF3 expression is correlated with metastatic potential in several cancers and inversely correlates with overall progression-free survival. Therefore, disruption of the WRC may serve as a novel strategy for targeting metastasis. Given the complexity involved in the formation of the WRC which is largely comprised of large protein-protein interfaces, there are currently no inhibitors for WASF3. However, several constrained peptide mimics of the various protein-protein interaction interfaces within the WRC were found to successfully disrupt WASF3-mediated migration and invasion. This review explores the role of the WASF3 WRC in driving metastasis and how it may be selectively targeted for suppression of metastasis.
KW - Metastasis
KW - Stapled peptide
KW - WASF Regulatory Complex
KW - Wiskott-Aldrich syndrome protein family 3
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U2 - 10.1016/j.phrs.2022.106302
DO - 10.1016/j.phrs.2022.106302
M3 - Review article
C2 - 35691539
AN - SCOPUS:85132340251
SN - 1043-6618
VL - 182
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 106302
ER -