Effects of integrin-mediated cell adhesion on plasma membrane lipid raft components and signaling

Andrés Norambuena1, Martin A Schwartz

  • 1Robert M. Berne Cardiovascular Research Center, Mellon Urological Cancer Research Institute, University of Virginia, Charlottesville, VA 22908, USA.

Insights

Cell adhesion loss triggers lipid raft changes, affecting growth signaling pathways. Specific proteins like flotillin2 and connexin43 remain membrane-bound, while Gα(s) detachment-induced cyclic adenosine monophosphate (cAMP) increase is blocked by modifying its lipid tail.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Anchorage dependence regulates cell growth and prevents cancer metastasis.
  • Integrin signaling and lipid rafts are crucial for cell adhesion.
  • Previous studies focused on limited lipid raft markers like GM1.

Purpose of the Study:

  • To investigate the behavior of diverse lipid raft components upon cell detachment.
  • To elucidate the mechanism linking cell adhesion, lipid raft dynamics, and cyclic adenosine monophosphate (cAMP) production.

Main Methods:

  • Analyzing lipid raft component localization and fractionation using sucrose gradients after cell detachment.
  • Investigating the role of Gα(s) lipid tail modification in regulating cAMP levels.

Main Results:

  • Many raft components internalized upon detachment, but flotillin2, connexin43, and H-Ras remained associated with the plasma membrane.
  • Loss of adhesion caused raft components to shift to non-raft fractions, with flotillin2, connexin43, and H-Ras showing resistance.
  • Gα(s) lost raft association, correlating with increased cAMP; modifying Gα(s) lipid tail prevented this cAMP elevation.

Conclusions:

  • Integrin-mediated adhesion influences the localization and behavior of various lipid raft components.
  • The study reveals a mechanism for the previously observed increase in cAMP following cell detachment, involving Gα(s) raft dissociation.

Related Concept Videos

Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Membrane Fluidity01:26

Membrane Fluidity

Membrane fluidity is explained by the fluid mosaic model of the cell membrane, which describes the plasma membrane structure as a mosaic of components—including phospholipids, cholesterol, proteins, and carbohydrates—that gives the membrane a fluid character.
Mosaic nature of the membrane
The mosaic characteristic of the membrane helps the plasma membrane remain fluid. The integral proteins and lipids exist as separate but loosely-attached molecules in the membrane. The membrane is a relatively...
Membrane Fluidity01:23

Membrane Fluidity

Cell membranes are composed of phospholipids, proteins, and carbohydrates loosely attached to one another through chemical interactions. Molecules are generally able to move about in the plane of the membrane, giving the membrane its flexible nature called fluidity. Two other features of the membrane contribute to membrane fluidity: the chemical structure of the phospholipids and the presence of cholesterol in the membrane.
Activation of Integrins01:15

Activation of Integrins

Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
Integrins01:10

Integrins

Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
Membrane Domains01:18

Membrane Domains

The membrane domains concentrate specific lipids and proteins at one place within the membrane, which helps in cell signaling, adhesion, and other critical cellular processes. These domains can differ in size, composition, function, and lifespan.
Protein Domains
The membrane comprises a group of distinct proteins responsible for carrying out a cell's specific function. For example, the plasma membrane of the human sperm, or a single germ cell, contains a unique set of proteins in the anterior...