The Cbl proteins are binding partners for the Cool/Pix family of p21‐activated kinase‐binding proteins

  title={The Cbl proteins are binding partners for the Cool/Pix family of p21‐activated kinase‐binding proteins},
  author={James Arthur Flanders and Qiyu Feng and Shubha Bagrodia and Maria T Laux and Avinash Singavarapu and Richard A. Cerione},
  journal={FEBS Letters},

Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool‐2/α‐Pix

It is shown that when Cool‐2 exists as a dimer, it functions as a Rac‐specific guanine nucleotide exchange factor (GEF), and novel mechanisms by which extracellular signals can direct the specific activation of Rac versus Cdc42 by Cool‐1/α‐Pix.

The Cbl family proteins: Ring leaders in regulation of cell signaling

This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects.

Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule βPix

This work shows that the SH3 domain of βPix specifically interacts with a proline–arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase, which provides a mechanism to fine-tune the kinetics of RTK endocytosis and degradation depending on the pool of active Cdc42 and the duration of EGFR signaling.

Cbl promotes clustering of endocytic adaptor proteins

These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation and ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation.

PAK family kinases

This chapter discusses what the authors know about the regulation of PAKs and their physiological role in different model organisms, based primarily on gene knockout „studies.

Cool-1 functions as an essential regulatory node for EGFreceptor- and Src-mediated cell growth

It is demonstrated that the regulated phosphorylation of Cool-1 is necessary to maintain the balance between normal signalling by EGFR and Src versus aberrant growth and transformation.

Regulation of Bin1 SH3 domain binding by phosphoinositides

It is suggested that the SH3‐mediated protein–protein interactions of Bin1 are regulated by Exon10 so that it may only occur when Bin1 localizes to certain submembrane areas.

A Novel Interaction between Atrophin-interacting Protein 4 and β-p21-activated Kinase-interactive Exchange Factor Is Mediated by an SH3 Domain*

The novel interaction between AIP4 andβPIX represents a new regulatory node for G protein-coupled receptor and receptor tyrosine kinase signal integration and provides important insight into the mechanistic basis for βPIX scaffolding of signaling components, especially those involved in cross-talk.



Regulation of the Cool/Pix Proteins

It is concluded that T1 represents a novel regulatory domain that accounts for the specific functional effects on PAK activity exhibited by the different members of the Cool/Pix family.

A Novel Regulator of p21-activated Kinases*

The identification of two closely related Pak3-binding proteins, possibly arising from alternative splicing, designated p50 and p85Cool-1 (cloned out of library) are reported, indicating a novel mechanism of regulation of Pak signaling.

Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene.

The data suggest that cbl-b encodes a protein which can interact with signal transduction proteins to regulate their function or to be regulated by them, which are members of a novel family of proto-oncogenes involved in signalTransduction.

Pak to the future.

Identification of a Mouse p21Cdc42/Rac Activated Kinase (*)

It is found that mPAK-3, expressed in vitro and in vivo, shows highly specific binding to the SH3 domain of phospholipase C- and at least one SH3domain in the adapter protein Nck, raising the possibility of an additional level of regulation of the PAK family in vivo.

Differential Effects of PAK1-activating Mutations Reveal Activity-dependent and -independent Effects on Cytoskeletal Regulation*

It was found that PAK1 kinase activity was associated with disassembly of focal adhesions and actin stress fibers and that this may require interaction with potential SH3 domain-containing proteins.

αPix Stimulates p21-activated Kinase Activity through Exchange Factor-dependent and -independent Mechanisms*

The data suggest that Pak activity can be modulated by physical interaction with αPix and that this specific effect involves both exchange factor-dependent and -independent mechanisms.