Abstract
The Hippo-YAP pathway is a central regulator of cell contact inhibition, proliferation and death. There are conflicting reports regarding the role of Angiomotin (Amot) in regulating this pathway. While some studies suggest a YAP-inhibitory function other studies indicate Amot is required for YAP activity. Here, we describe an Amot-dependent complex comprised of Amot, YAP and Merlin. The phosphorylation of Amot at Serine 176 shifts localization of this complex to the plasma membrane, where it associates with the tight-junction proteins Pals1/PATJ and E-cadherin. Conversely, hypophosphorylated Amot shifts localization of the complex to the nucleus, where it facilitates the association of YAP and TEAD, induces transcriptional activation of YAP target genes and promotes YAP-dependent cell proliferation. We propose that phosphorylation of AmotS176 is a critical post-translational modification that suppresses YAP's ability to promote cell proliferation and tumorigenesis by altering the subcellular localization of an essential YAP co-factor.
Highlights
Angiomotin (Amot) was originally identified as an angiostatin-binding protein involved in the regulation of endothelial cell polarization, migration, proliferation, and angiogenesis (Kikuno et al, 1999; Levchenko et al, 2003; Troyanovsky et al, 2001)
We first thought to assess whether Amot-p130, YAP and Merlin form a complex and subsequently whether this is dependent on Angiomotin phosphorylation
Overall our findings demonstrate that while AmotS176 phosphorylation does not impact the formation of the Amot/YAP/Merlin complex, it mediates the localization of the complex through phosphorylation of Serine 176 that leads to recruitment of the complex to the plasma membrane or a shift to a nuclear localization in the hypophosphorylated state
Summary
Angiomotin (Amot) was originally identified as an angiostatin-binding protein involved in the regulation of endothelial cell polarization, migration, proliferation, and angiogenesis (Kikuno et al, 1999; Levchenko et al, 2003; Troyanovsky et al, 2001). Amot is required for endothelial cell migration, by binding to the Syx:Patj/Mupp polarity complex to localize RhoA activity to the leading edge of migratory cells (Ernkvist et al, 2009). It has been implicated in epithelial cell polarity, as an inhibitor of the GTPase-Activating Protein (GAP) Rich and shown to compromise the integrity of tight junctions by promoting Rich1mediated hydrolysis of Rho GTPases Rac and Cdc (Wells et al, 2006; Yi et al, 2011).
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