Pathway Map Details

Cytoskeleton remodeling_Role of PKA in cytoskeleton reorganisation



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Actin cytoskeletal, LBC, BETA-PIX, cAMP, c-Abl, PAK1, Beta adducin, LIMK1, CDC42, PLC-beta3, G-protein alpha-s, ROCK, 14-3-3 beta/alpha, 3.1.4.11, Ca(2+) endoplasmic reticulum lumen, LASP1, MLCP (reg), alpha-4/beta-1 integrin, DAG, Cofilin, RhoA, PKA-cat (cAMP-dependent), Paxillin, Rac1, IP3, Adenylate cyclase, 4.6.1.1, PKA-reg (cAMP-dependent), Fodrin (spectrin), ATP cytosol, Calmodulin, Ca(2+) cytosol, Ca('2+) = Ca('2+), G-protein beta/gamma, MLCK, VASP, Alpha adducin, MELC, IP3 receptor, MLCP (cat)

Description:

Role of PKA in cytoskeleton reorganisation

A wide variety of soluble signaling mediators utilize the Protein kinase cAMP-dependent ( PKA ) pathway to regulate cellular processes including intermediary metabolism, ion channel conductivity, and transcription. PKA plays a central role in cytoskeletal regulation and cell migration. Moreover, the role of PKA in cytoskeletal organization and cell migration, exerting both negative (i.e. inhibitory) and positive (i.e. required or enhancing) effects.

GNAS complex locus coupled receptor ( G-protein alpha-s coupled receptor ) interaction with the trimeric G-protein alpha-s/ Guanine nucleotide binding protein beta and gamma ( G-protein beta/gamma ) causes the exchange of GDP for GTP bound to G-protein alpha subunits and the dissociation of the G-protein beta/gamma heterodimers. G-protein alpha-s activates Adenylate cyclases.

Upon stimulation, Adenylate cyclases increase the level of Cyclic Adenosine 3',5'-monophosphate ( cAMP ) in cells and activate the PKA-cat and PKA-reg complex that results in PKA activation [1].

Negative effects of PKA on cell migration have been reported for integrin-dependent endothelial cell migration. Also, matrix-specific down-regulation of cAMP/ PKA signaling appears to be required for collagen-induced Actin synthesis and stress fiber formation in endothelial cells [2].

PKA -dependent phosphorylation of complex Integrin alpha 4 and beta 1 ( Alpha-4/beta-1 integrin ) is important for migration and other integrin function. Phosphorylation of Alpha-4/beta-1 integrin blocks Paxillin binding, which activates cell migration and increases lamellipodial stability [3].

The cytoskeletal regulatory protein Vasodilator-stimulated phosphoprotein ( VASP ) localizes to focal adhesions, largely through interaction with proteins such as Vinculin, Zyxin, and KIAA1274. PKA phosphorylates VASP and disrupts its interaction with C-abl oncogene 1 receptor tyrosine kinase ( c-Abl ) [4].

A relative newcomer to the list, the LIM and SH3 protein 1 ( LASP1 ), was identified as a potential cytoskeletal PKA substrate in gastric fibroblasts and gastric parietal cells. LASP1 regulates its translocation to areas of dynamic actin filaments synthesis. Phosphorylation of LASP1 by PKA decreases its interaction with Actin [5].

Adducin s promote association of Spectrin non-erythrocytic ( Fodrin (spectrin) ) with Actin to facilitate capping of the fast growing end of Actin filaments. PKA phosphorylates Alpha adducin and Beta adducin and reduces their affinity for Fodrin (spectrin)/ Actin complexes as well as the activity of Adducin s in promoting binding of Fodrin (spectrin) to Actin filaments [6].

PKA directly phosphorylates monomeric Actin, which causes a significant decrease in monomer 'polymerizibility'.

Myosin-based contractility is important for several aspects of cell movement, including retraction of the trailing edge and less well-defined functions within the leading edge, where Myosin light chain ( MELC ) interaction with Actin and myosin-dependent contractility are positively regulated by phosphorylation. MELC phosphorylation is proximally controlled by the ratio of Myosin light chain kinase ( MLCK ) and Protein phosphatase 1 catalytic subunit beta isoform ( MLCP ) activities. The regulation of MLCK and MLCP is intensely complex, and involves cAMP -dependent PKA signaling. MLCK is activated by the Ca(2+)/ Calmodulin binding. PKA can regulate Ca(2+) release through phosphorylation and inhibition of Phospholipase C ( PLC-beta ), resulting in the inactivation of receptors for Inositol trisphosphate ( IP3 ). cAMP and PKA can up-regulate MLCP activity through the Rho-associated, coiled-coil containing protein kinase ( ROCK )-dependent inhibition of MLCP phosphorylation and inhibition of Ras homolog gene family, member A ( RhoA ). The influence of PKA on MLCK and MLCP has the same effect on decreasing MELC phosphorylation and stress fibers formation [2].

A kinase (PRKA) anchor protein 13 ( LBC ) activity can be inhibited by the anchoring both PKA and Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta polypeptide ( 14-3-3 beta/alpha ) proteins. LBC has a close functional link with the actin cytoskeleton through its interaction with the RhoA and ability to promote G-protein coupled receptors-dependent stress fiber formation.

Conversely, elevation of cAMP level and activation of PKA have been shown to be required for efficient cell migration, or hallmark steps of migration, in several systems as well. These include: formation of filopodia and lamellipodia, which are governed by the activation of Cell division cycle 42 ( CDC42 ) and Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) respectively. Stimulation of PKA by cAMP results in Rho guanine nucleotide exchange factor 7 ( BETA-PIX ) phosphorylation, which in turn controls BETA-PIX translocation to focal complexes and Rac1 and CDC42 activation [7].

References:

  1. Defer N, Best-Belpomme M, Hanoune J
    Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. American journal of physiology. Renal physiology. 2000 Sep;279(3):F400-16
  2. Howe AK
    Regulation of actin-based cell migration by cAMP/PKA. Biochimica et biophysica acta 2004 Jul 5;1692(2-3):159-74
  3. Han J, Rose DM, Woodside DG, Goldfinger LE, Ginsberg MH
    Integrin alpha 4 beta 1-dependent T cell migration requires both phosphorylation and dephosphorylation of the alpha 4 cytoplasmic domain to regulate the reversible binding of paxillin. The Journal of biological chemistry 2003 Sep 12;278(37):34845-53
  4. Lebrand C, Dent EW, Strasser GA, Lanier LM, Krause M, Svitkina TM, Borisy GG, Gertler FB
    Critical role of Ena/VASP proteins for filopodia formation in neurons and in function downstream of netrin-1. Neuron 2004 Apr 8;42(1):37-49
  5. Keicher C, Gambaryan S, Schulze E, Marcus K, Meyer HE, Butt E
    Phosphorylation of mouse LASP-1 on threonine 156 by cAMP- and cGMP-dependent protein kinase. Biochemical and biophysical research communications 2004 Nov 5;324(1):308-16
  6. Matsuoka Y, Hughes CA, Bennett V
    Adducin regulation. Definition of the calmodulin-binding domain and sites of phosphorylation by protein kinases A and C. The Journal of biological chemistry 1996 Oct 11;271(41):25157-66
  7. Chahdi A, Miller B, Sorokin A
    Endothelin 1 induces beta 1Pix translocation and Cdc42 activation via protein kinase A-dependent pathway. The Journal of biological chemistry 2005 Jan 7;280(1):578-84