Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

Abstract

Infiltration of macrophages into tissue can promote tumour development. Depending on the extracellular matrix architecture, macrophages can adopt two migration modes: amoeboid migrationcommon to all leukocytes, and mesenchymal migration -restricted to macrophages and certain tumour cells. Here, we investigate the initiating mechanisms involved in macrophage mesenchymal migration. We show that a single macrophage is able to use both migration modes. Macrophage mesenchymal migration is correlated with decreased activity of Rho/Rho-associated protein kinase (ROCK) and is potentiated when ROCK is inhibited, suggesting that amoeboid inhibition participates in mechanisms that initiate mesenchymal migration. We identify the cyclindependent kinase (CDK) inhibitor p27 kip1 (also known as CDKN1B)as a new effector of macrophage 3D-migration. By using p27 kip1 mutant mice and small interfering RNA targeting p27 kip1 , we show that p27 kip1 promotes mesenchymal migration and hinders amoeboid migration upstream of the Rho/ROCK pathway, a process associated with a relocation of the protein from the nucleus to the cytoplasm. Finally, we observe that cytoplasmic p27 kip1 is required for in vivo infiltration of macrophages within induced tumours in mice. This study provides the first evidence that silencing of amoeboid migration through inhibition of the Rho/ROCK pathway by p27 kip1 participates in the onset of macrophage mesenchymal migration.

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“…Activated Rho promotes the actin stress fiber formation and the cell attachment. 22) It was reported that the Rho and/ or Rho kinase are involved in the cell migration inhibition of macrophage, 23) B-cell lymphoma 24) and vascular smooth muscle.…”

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“…Factors influencing this switch are mainly pore size of the matrix and the deformability of the cell nucleus [111][112][113][114]. Moreover, acquisition of a mesenchymal migration mode by macrophages has been shown to involve downregulation of Rho/ROCK signaling by the cyclin-dependent kinase p27 kip1 [115].…”

p27Kip1 promotes invadopodia turnover and invasion through the regulation of the PAK1/Cortactin pathway

“…Consequently, mouse embryo fibroblasts (MEFs) lacking p27 have more RhoA activity, increased numbers of stress fibers and focal adhesions and exhibit a defect in migration (Besson et al, 2004b). This pathway is important for proper migration of bone marrow macrophages and developing cortical neurons and for cancer cell migration and invasion in vivo (Godin et al, 2012; Nguyen et al, 2006; Papakonstanti et al, 2007; Gui et al, 2014; Wu et al, 2006; See et al, 2010; Larrea et al, 2009; Jin et al, 2013). p27 can also regulate cell migration by controlling microtubule stability through Stathmin or directly by binding to microtubules and promoting microtubule polymerization (Baldassarre et al, 2005; Godin et al, 2012).…”

“…The mode of migration is influenced, at least in part, by the activities of Rho GTPases: RhoA activity favors an amoeboid migration, whereas Rac1 activity promotes mesenchymal migration (Sahai and Marshall, 2003; Vial et al, 2003). Accordingly, cytoplasmic p27 promotes mesenchymal migration via the inhibition of RhoA activity, while cells lacking p27 tend to adopt an amoeboid mode of migration (Gui et al, 2014; Belletti et al, 2010). More recently, p27 was reported to promote epithelial to mesenchymal transition by binding to JAK2, promoting STAT3 activation and the upregulation of Twist1 (Zhao et al, 2015).…”