Cell-Type-Specific Activation of PAK2 by Transforming Growth Factor β Independent of Smad2 and Smad3

Abstract

Transforming growth factor ␤ (TGF-␤) causes growth arrest in epithelial cells and proliferation and morphological transformation in fibroblasts. Despite the ability of TGF-␤ to induce various cellular phenotypes, few discernible differences in TGF-␤ signaling between cell types have been reported, with the only well-characterized pathway (the Smad cascade) seemingly under identical control. We determined that TGF-␤ receptor signaling activates the STE20 homolog PAK2 in mammalian cells. PAK2 activation occurs in fibroblast but not epithelial cell cultures and is independent of Smad2 and/or Smad3. Furthermore, we show that TGF-␤-stimulated PAK2 activity is regulated by Rac1 and Cdc42 and dominant negative PAK2 or morpholino antisense oligonucleotides to PAK2 prevent the morphological alteration observed following TGF-␤ addition. Thus, PAK2 represents a novel Smad-independent pathway that differentiates TGF-␤ signaling in fibroblast (growth-stimulated) and epithelial cell (growth-inhibited) cultures.

A Unique Element in the Cytoplasmic Tail of the Type II Transforming Growth Factor-β Receptor Controls Basolateral Delivery

“…The R-Smad/Smad4 complex subsequently translocates to the nucleus where it can function as a comodulator of transcription (Ten Dijke et al, 2002;Shi and Massagué, 2003). In addition to the aforementioned Smad-dependent pathways, Smad-independent responses have also been documented critical for many aspects of TGF␤ signaling, including cell proliferation and morphological transformation (Hocevar et al, 1999;Wilkes et al, 2003).…”

“…The R-Smad/Smad4 complex subsequently translocates to the nucleus where it can function as a comodulator of transcription (Ten Dijke et al, 2002;Shi and Massagué, 2003). In addition to the aforementioned Smad-dependent pathways, Smad-independent responses have also been documented critical for many aspects of TGF␤ signaling, including cell proliferation and morphological transformation (Hocevar et al, 1999;Wilkes et al, 2003).Although the type I and type II TGF␤ receptors show a relatively homogeneous distribution over the cell surface of fibroblasts (Ehrlich et al, 2001;Yao et al, 2002), we have shown that both receptors localize to the basolateral domains in polarized epithelium (Murphy et al, 2004). Because basolateral trafficking for both receptors was independently regulated and mediated by sequences in the cytoplasmic tails of the receptors (Murphy et al, 2004), a further definition of the presumptive cis-acting element(s) was required.…”

p21-activated Kinase 2 (PAK2) Inhibits TGF-β Signaling in Madin-Darby Canine Kidney (MDCK) Epithelial Cells by Interfering with the Receptor-Smad Interaction

“…Although the canonical Smad pathway was shown not to be affected by PAK2 in fibroblasts (23), it remains unclear whether PAK2 has any effect in other types of cells. In the present study, we report that PAK2 restricts TGF-␤-elicited phosphorylation and transcriptional activities of R-Smads in madine-darby canine kidney (MDCK) epithelial cells.…”

“…Several substrates of PAK2 have been identified in various contexts and mediate its wide range of cellular events, from cytoskeletal rearrangements to survival promotion and cellular transformation (19,22). Interestingly, PAK2 was reported to mediate TGF-␤ signaling in mesenchy-mal cells, but not in epithelial cells (23)(24)(25). The cell type-specific activation of PAK2 by TGF-␤ is controlled by the tumor suppressor Merlin and an epithelial-specific protein Erbin, both of which form a complex and inactivate PAK2 through blocking Cdc42/Rac1 binding in epithelial cells (26).…”

Autocrine transforming growth factor-β regulation of hematopoiesis: many outcomes that depend on the context

“…It has also been shown that BMPs can regulate the development of human hematopoietic stem cells, presumably through the BMPactivated Smad proteins, Smad1 and Smad5, which they expressed in HSC (Bhatia et al, 1999). In addition, several Smad-independent pathways have been identified (Engel et al, 1999;Yue and Mulder, 2001;Wilkes et al, 2003). The TGF-b-activated receptor complex can signal through AKT, mitogen-activated protein kinases (MAPKs), the phoshoinositol-3-kinase (PI3K) and the PP2A/p70s65K pathways (Wakefield and Roberts, 2002).…”