Biology subjects

Rohena, C.

Publications and source records attributed to Rohena, C..

3 recordsLinked to original sources

bioRxiv2021

GIV/Girdin, a Non-receptor Modulator for Gαi/s, Regulates Spatiotemporal Signaling during Sperm Capacitation and is Required for Male Fertility

For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract, and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of KO mice and cell-penetrating peptides, we show that GIV (CCDC88A), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine spermatozoa. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K[->] Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testis and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and shed light on a hitherto unforeseen cause of infertility in men. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/442927v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@f4901forg.highwire.dtl.DTLVardef@2211dforg.highwire.dtl.DTLVardef@c37ff5org.highwire.dtl.DTLVardef@105eed7_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIGIV is highly expressed in spermatozoa, and is required for male fertility C_LIO_LIGIV is rapidly phosphoregulated during sperm capacitation C_LIO_LIIt enhances tyrosine-based signals in sperm tail, enhances motility C_LIO_LIIt suppresses cAMP in the sperm head, inhibits premature acrosome exocytosis C_LI

cell biology↗

bioRxiv2019

GIV-Kindlin interaction is required for Kindlin-Mediated Integrin Recognition and Activation

Cells perceive and respond to the extracellular matrix (ECM) via integrin receptors; their dysregulation has been implicated in inflammation and cancer metastasis. Here we show that a guanine nucleotide exchange modulator of trimeric-GTPase Gi, GIV (a.k.a Girdin), directly binds the integrin adaptor Kindlin-2. A non-canonical short linear motif within GIVs C-terminus binds Kindlin-2-FERM3 domain at a site that is distinct from the binding site for the canonical NPxY motif on the -integrin tail. Binding of GIV to Kindlin-2 allosterically enhances Kindlin-2s affinity for {beta}1-integrin. Consequently, integrin activation and clustering are maximized, which augments cell adhesion, spreading and invasion. Findings elucidate how the GIV*Kindlin-2 complex has a two-fold impact: it allosterically synergizes integrin activation and enables {beta}1-integrins to indirectly access and modulate trimeric GTPases via the complex. Furthermore, Cox proportional-hazard models on tumor transcriptomics provide trans-scale evidence of synergistic interactions between GIV*Kindlin-2*{beta}1-integrin on time to progression to metastasis. The eTOC blurbIntegrins mediate cell adhesion to the extracellular matrix; their dysregulation fuels inflammation, cancer cell invasion and metastasis. Authors show how two pro-metastatic scaffold proteins, Kindlin and GIV/Girdin bind and cooperatively enhance their allosteric coupling to integrins, and their subsequent activation. Findings reveal novel interfaces in integrin signaling for pharmacologic manipulation. HIGHLIGHTSO_LIGIV and Kindlin(K2), two integrin adaptors that promote metastasis, bind each other C_LIO_LIBinding of GIV or integrin to K2 allosterically enhances GIV*K2*integrin complexes C_LIO_LIBinding is required for the maximal recruitment of GIV and K2 to active integrins C_LIO_LIBinding facilitates integrin clustering, activation, tumor cell adhesion, invasion. C_LI

cell biology↗

bioRxiv2019

GIV/Girdin and Exo70 Constitute the Core of the Mammalian Polarized Exocytic Machinery

Polarized exocytosis is a fundamental process by which membrane and cargo proteins are delivered to the plasma membrane with precise spatial control; it is essential for cell growth, morphogenesis, and migration. Although the need for the octameric exocyst complex is conserved from yeast to humans, what imparts spatial control is known only in yeast, i.e., a polarity scaffold without mammalian homolog, called Bem1p. We demonstrate that polarity scaffold GIV/Girdin fulfills the key criteria and functions of its yeast counterpart Bem1p. Both Bem1p and GIV bind yeast and mammalian Exo70 proteins via similar short-linear interaction motifs, but each preferentially binds its evolutionary counterpart. In cells where this GIV*Exo-70 interaction is selectively disrupted, delivery of the metalloprotease MT1-MMP to podosomes, collagen degradation and haptotaxis through basement membrane matrix were impaired. GIVs interacting partners reveal other components of polarized exocytosis in mammals. Findings not only expose how GIV "upgrades" the exocytic process in mammals, but also how the ability to regulate exocytosis shapes GIVs ability to fuel metastasis. GRAPHIC ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY Graphic Abstract: Schematic comparing the components of polarized exocytosis, i.e., the major polarity scaffold in yeast (Bem1p; left) and humans (Girdin; right) and the various cellular components and signaling mechanisms that are known to converge on them. C_FIG_DISPLAY The eTOC blurbPolarized exocytosis is a precision-controlled process that is enhanced in disease states, e.g., cancer invasion; what imparts polarity was unknown. Authors reveal how the process underwent an evolutionary upgrade from yeast to humans by pinpointing GIV/Girdin as the polarity scaffold which orchestrates the exocytosis of matrix metalloproteases during cell invasion. HIGHLIGHTSO_LIGIV (human) and Bem1p (yeast) bind Exo70; are required for exocytosis C_LIO_LIGIV binds and aids PM localization Exo70 via a conserved short linear motif C_LIO_LIBinding facilitates MT1-MMP delivery to podosomes, ECM degradation, invasion C_LIO_LIRegulatory control over polarized exocytosis is upgraded during evolution C_LI

cell biology↗