Rac‐<scp>GTP</scp>ases and Rac‐<scp>GEF</scp>s in neutrophil adhesion, migration and recruitment

Pantarelli, Chiara; Welch, Heidi

doi:10.1111/eci.12939

Cited by 42 publications

(41 citation statements)

References 69 publications

(176 reference statements)

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“…Other than CXCL16, IL-8 was another increased chemokine from HMGB1-treated keratinocytes; this result is consistent with the findings reported by Dejean et al (2012). IL-8 is known to induce the chemotaxis for neutrophils; however, the migration of neutrophils depends not only on the chemotactic function of IL-8 but also on the polarity of neutrophils, which is mediated by Rho GTPases (Pantarelli and Welch, 2018). Recently, some studies have found that 8-hydroxydeoxyguanosine, an oxidative stresseinduced DNA product that is elevated in vitiligo (Vaseghi et al, 2017;Wei et al, 2013), could inhibit the function of Rho GTPases (Park et al, 2017).…”

Section: Discussionsupporting

confidence: 90%

Oxidative Stress–Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo

Cui

Zhang

et al. 2019

Journal of Investigative Dermatology

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Vitiligo is a cutaneous depigmentation disorder caused by the destruction of epidermal melanocytes. The generation and the skin infiltration of autoreactive CD8 þ cytotoxic T cells triggered by oxidative stress play a critical role in vitiligo. High-mobility group protein B1 (HMGB1) is a classic damage-associated molecular pattern molecule with strong proinflammatory effects in inflammatory reactions. A previous study reported an enhanced expression of HMGB1 in vitiligo lesions, but the role of HMGB1 in cutaneous inflammation of vitiligo is still unknown. In the present study, we initially found that HMGB1 was released from the nucleus of melanocytes in vitiligo perilesional skin. Furthermore, cultured normal human melanocytes could release HMGB1 under treatment with hydrogen peroxide. Moreover, HMGB1 facilitated the secretion of CXCL16 and IL-8 from keratinocytes by binding to the receptor for advanced glycation end products and activating NF-kB and extracellular signaleregulated kinase signaling pathways. Subsequently, HMGB1 led to the formation of chemotaxis for the migration of CD8 þ T cells from patients with vitiligo by increasing the release of CXCL16 from keratinocytes. Additionally, HMGB1 promoted the maturation of dendritic cells from patients with vitiligo. Altogether, our study demonstrates that HMGB1 released from melanocytes contributes to the formation of oxidative stresseinduced autoimmunity in vitiligo.

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Section: Discussionsupporting

confidence: 90%

Oxidative Stress–Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo

Cui

Zhang

et al. 2019

Journal of Investigative Dermatology

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“…AP-1 is also a transcription factor and regulates differentiation, proliferation and apoptosis of the cell [43]. Chemokine-triggered β2 integrin activation can transduce signaling over small GTPases, Rap [27] and/or Rho (Ras homolog gene) [39], Rac-1 (Ras-related C3 botulinum toxin substrate 1) [44], Cdc42 (Cell division control protein 42 homolog) [45], according Rho-GEF such as, CALDAG-GEF [46], DOCK2 (Dedicator of cytokinesis 2) [47], VAV1 (Vav Guanine Nucleotide Exchange Factor 1) [48], kinases, including STK4 (Serine/threonine-protein kinase 4) and SKAP55 (Src kinase-associated phosphoprotein 5) [49], and other signaling proteins like PLD1 (Phospholipase D1) [50] and adaptor proteins as ADAP (Adhesion and degranulation-promoting adaptor protein) [49] and PIP5K1C (Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Gamma) [51,52]. Altogether, inside-out signaling induces a conformational change of the β2 integrin, leading to a high affinity open state, which results in strong binding of all ligands [53].…”

Section: Activation Of β2 Integrinsmentioning

confidence: 99%

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

Bednarczyk

Stege

Grabbe

et al. 2020

IJMS

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β2 integrins are heterodimeric surface receptors composed of a variable α (CD11a-CD11d) and a constant β (CD18) subunit and are specifically expressed by leukocytes. The α subunit defines the individual functional properties of the corresponding β2 integrin, but all β2 integrins show functional overlap. They mediate adhesion to other cells and to components of the extracellular matrix (ECM), orchestrate uptake of extracellular material like complement-opsonized pathogens, control cytoskeletal organization, and modulate cell signaling. This review aims to delineate the tremendous role of β2 integrins for immune functions as exemplified by the phenotype of LAD-I (leukocyte adhesion deficiency 1) patients that suffer from strong recurrent infections. These immune defects have been largely attributed to impaired migratory and phagocytic properties of polymorphonuclear granulocytes. The molecular base for this inherited disease is a functional impairment of β2 integrins due to mutations within the CD18 gene. LAD-I patients are also predisposed for autoimmune diseases. In agreement, polymorphisms within the CD11b gene have been associated with autoimmunity. Consequently, β2 integrins have received growing interest as targets in the treatment of autoimmune diseases. Moreover, β2 integrin activity on leukocytes has been implicated in tumor development.

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“…Small GTP-binding proteins, also denoted small G proteins, are 20-40 kDa GTPases that participate in many signaling pathways controlling a plethora of cellular functions (reviewed in [164][165][166]). Interestingly, a protein denoted Trio has two guanine nucleotide-exchange factor (GEF) domains, one specific for Rac and the other for Rho, and a protein kinase domain similar to the one in CaMK.…”

Section: Cam-regulated Small G Proteinsmentioning

confidence: 99%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

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Rac‐GTPases and Rac‐GEFs in neutrophil adhesion, migration and recruitment

Cited by 42 publications

References 69 publications

Oxidative Stress–Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo

Oxidative Stress–Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

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